OSU Neurology RITE Gene Guide – Flashcards

Agenesis of the corpus callosum abdominal problems Infantile Spasms Retinal abnormalities Hydrocephalus Umbilical hernias Boys (XXY), usually females Aicardi syndrome is a rare genetic malformation syndrome characterized by the partial or complete absence of a key structure in the brain called the corpus callosum, the presence of retinal abnormalities (lacunae or coloboma), and seizures in the form of infantile spasms. Aicardi syndrome is theorized to be caused by a defect on the X chromosome as it has thus far only been observed in girls or in boys with Klinefelter's syndrome (XXY). Symptoms typically appear before a baby reaches about 5 months of age. Usually appear around 3 months of age. Can also see hydrocephaly, porencephalic cysts, microcephaly. GI abnormalities include hernias, feeding difficulties possibly needing feeding tube and fundoplication. Most patients develop developmental delay, mostly moderate mental retardation.

axonal neuropathy. There are 6 different subtypes a to f shown by linkage analysis. HMSN IIa - MFN2 and K1F1B mutations. HMSN IIb: RAB7 mutation. HMSN IID: GARS mutation; HMSN IIe: NFL mutation. Most don't have an identifiable genes, except MFN 2 gene. This is a nuclear gene that encodes mitochondrial protein mitofusin 2. When this is deficient, results in an inability of mitochondria to fuse or move along microtubules during fast anterograde axonal transport and depriving the distal axon of an energy source. Difficult to distinguish from CMT type I without NCS. Presents later in life and develop less upper limb weakness than CMT type I. May be mistaken for idiopathic sensorimotor peripheral neuropathy. In HMSN IIb, have severe sensory loss. In HMSN IIc, get diaphragm and/or vocal cord paralysis. In HMSN IId: upper limb involvement early in disease course. On EMG/NCS, have reduced SNAPs and CMAPs with EMG evidence of reinnervation and mild denervation. Can have high arched feet. No treatment except symptomatic.

These are X linked recessive. Theare is an abnormality of the dystrophin complex which weakens the sarcolemma with subsequent muscle fiber necrosis. On DNA analysis, have large deletions, duplications and small deletions/point mutations. Have normal height/weight at birth and subsequent decrease in height/weight. Patients also get motor developmental delay with difficulty in running, climbing. As a child, notice to walk on toes and difficulty rising from the floor. Can have a positive Gowers sign in which patient stand sup by using hands pushing on knees. At age 5-6 years, have pseudohypertrophy of the calves. By 12 years of age, have loss of ambulation, atrophy of all muscles and contractures (ankles, knees and hips). Get progressive kyphoscoliosis and exaggerated lumbar lordosis after loss of ambulation. Progress to death by age 15-30 years. Muscle weakness is usually more proximal than distal and both upper and lower extremities are involved. There is a scapuloperoneal distribution involvement including proximal muscles, anterior tibialis, peronei muscle groups, neck flexors, wrist and digit extensors. Can involve respiratory muscle involvement. There is preservation of cranial musculature. At risk for malignant hyperthermia under general anesthesia and for rhabdomyolysis. Can get cardiomyopathy developing into CHF and arrhythmias. Can also get intestinal pseudoobstruction of smooth muscles of GI tract. CK is usually elevated early, but decreases with disease progression. In Becker DM, there is a later age of onset, less severs and later progression compared to DMD. Usual age of onset if 5-15 years. Ambulate beyond 15 years of age and have loss of ambulation in 4th decade. Age of death is 30-60 y/o. On pathology, there is abnormal variation in muscle fiber size, hpercontracted muscle fibers, macrophage invasion, progressive loss of muscle fiber and replacement with connective tissues. In DMD, there is absence of dystrophin on staining and altered staining patterns on BMD. On EMG, shows increased insertional activity, small myopathiic MUP in affected muscle groups. In asymptomatic patients, can sees normal insertional activity. With progression, can see CMAP that are decreased and reduced recruitment. Treatment includes steroids and genetic counseling

characterized by progressive hearing loss/deafness and vision loss. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. Night vision loss begins first, followed by blind spots that develop in the side (peripheral) vision. Over time, these blind spots enlarge and merge to produce tunnel vision. In some cases of Usher syndrome, vision is further impaired by clouding of the front surface of the eye (cataracts). Many people with retinitis pigmentosa retain some central vision throughout their lives. People with Usher syndrome type III experience progressive hearing loss and vision loss beginning in the first few decades of life. Unlike the other forms of Usher syndrome, infants with Usher syndrome type III are usually born with normal hearing. Hearing loss typically begins during the first two decades of life, after the development of speech, and progresses over time. By middle age, most affected individuals are profoundly deaf. Vision loss caused by retinitis pigmentosa develops in late childhood or adolescence. People with Usher syndrome type III may also experience difficulties with balance due to inner ear problems. Inherited in an Autosomal Dominant pattern. Mutations in at least two genes are responsible for Usher syndrome type III; however, CLRN1 is the only gene that has been identified.

Usher syndrome type II is characterized by hearing loss from birth and progressive vision loss that begins in adolescence or adulthood. The hearing loss associated with this form of Usher syndrome ranges from mild to severe and mainly affects high tones. Affected children have problems hearing high, soft speech sounds, such as those of the letters d and t. The degree of hearing loss varies within and among families with this condition. Unlike other forms of Usher syndrome, people with type II do not have difficulties with balance caused by inner ear problems. Autosomal Dominant Inheritance. Usually has same vision abnormalities as RP 3 (described above). Usher syndrome type II is caused by mutations in at least four genes. Only two of these genes, USH2A and GPR98 (also called VLGR1), have been identified.

X linked recessive inheritance. This is the most common form of urea cycle disorders. Elevated ammonia leads to astrocyte swelling from glutamine accumulation, leading to brain edema acutely. Triad of hyperammonemia, encephalopathy and respiratory alkalosis occurs and is due to hyperventilation. In neonatal onset, symptoms present within 24-72 hours of life and usually occur in a term infant. Get vomiting, poor feeding, apnea, hypothermia and lethargy followed by coma and seizures. Severity of encephalopathy correlated with ammonia level. In late onset, symptoms are associated with infections and high protein meals. Get hyperammonemia, vomiting, altered mental status, ataxia and amblyopia. Also seizures, developmental delay and growth retardation. Female carriers of OTC deficiency can present postpartum with hyperammonemic encephalopathy (possibly episodic). Other symptoms include spastic quadriplegia, seizures, MR, hyperactivity and growth failure. Diagnose in newborns with hyperammonemia without organic academia and analysis of quantitative amino acids in plasma and urine and measurement of organic acids and orotic acid. Enzyme defect in peripheral leukocytes or hepatocytes is confirmatory. Imaging shows cerebral edema during acute encephalopathy. LFTs are normal. On pathology, show cerebral edema with astrocyte swelling and Alzheimer type II cells. For management, all dietary and parenteral nitrogen intake must be discontinued in acute hyperammonemia. Give IV sodium benzoate, dodrium phenyalcetate, 10% arginine hydrochloride should be given immediately in OTC with a priming dose. May need hemodialysis if hyperammonemia lasts greater than 8 days. With increased ICP, give mannitol. Do not hyperventilate, as can cause decreased cerebral blood flow due to hypocapnia. In the long term, need low protein diet, essential amino acid mixture, citrulline supplementation for OTC . May need liver transplantation. At high risk for neurological deficits. In late onset, stabilize at level of neurological function at time of therapy onset. Can diagnose prenatally through DNA analysis and enzyme analysis in amniocytes and chorionic villi cells.

(X linked recessive) that primarily affects the eye and almost always leads to blindness. In addition to the congenital ocular symptoms, some patients suffer from a progressive hearing loss starting mostly in their 2nd decade of life, while another portion may be mentally challenged. Patients with Norrie Disease may develop cataracts, leukocoria (a condition where the pupils appear white when light is shone on them), along with other developmental issues in the eye, such as shrinking of the globe and the wasting away of the iris. Around 30-50% of them will also have developmental delay/mental retardation, psychotic-like features, ataxia or behavioral abnormalities.[1] Most patients are born with normal hearing; however, the onset of hearing loss is very common in early adolescence. About 15% of the patients are estimated to develop all the features of the disease. The disease affects almost only male infants at birth or soon after birth. Norrie Disease is a genetic disorder caused by mutations in the NDP gene coding for the protein Norrin, located on Xp11.4 (GeneID: 4693). It is inherited in an X-linked recessive way from usually one of your parents. Norrin also appears to be crucial in the specialization of the cells of the retina and the establishment of a blood supply to the inner ear and the tissues of the retina. The role of norrin in the specialization of retinal cells for their unique sensory is interfered by the mutation of NDP. This results in an accumulation of immature retinal cells in the back of the eye. When norrin's role in the establishment of blood vessels supplying the eye is disrupted, eventually the tissues will break down Sons of affected men will not have the mutation, while all of their daughters will be genetic carriers of the mutation. They also usually show no clinical symptoms, but will inherit the mutation to 50% of their offspring. Daughters receiving the mutated gene will also be, like their mother, asymptomatic carriers, but 50% of their sons will express clinical symptoms. Females are very unlikely to express clinical signs. One possible scenario leading to this (unlikely) case would be if both of their copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous somatic mutation. Another explanation for affected females could be skewed X-Chromosome inactivation. The most prominent symptoms of Norrie Disease are ocular. The first visible finding is Leukocoria, a grayish-yellow pupillary reflex that originates from a mass of unorganized tissue behind the lens. This material, which possibly includes an already detached retina, may be confused with a tumor and thus is termed pseudoglioma. However, an affected baby may have a normally sized eye globe and inconspicuous iris, anterior chamber, cornea and intraocular pressure. Over the first few months of life, complete or partial retinal detachment evolves. From the time they're a baby through childhood, the patient may undergo progressive changes in the disease. These progressions include the formation of cataracts, deterioration of the iris with adhesions forming between the iris and the lens or the cornea, and shallowing of the anterior chamber which increases intraocular pressure that can become painful. As the situation worsens, there is corneal opacification, where the cornea becomes opaque, and band keratopathy. Intraocular pressure is lost and the globe shrinks. In the last stage of Norrie disease, the globes appear small and sunken in (phthisis bulbi) and the cornea appears to be milky . Norrie disease can also have cognitive and behavioral symptoms. Developmental delay and mental retardation are present in about 30-50% of males who have Norrie disease.[1] Psychotic-like features and poorly characterized behavior abnormalities may also be present. Auditory symptoms are often common with Norrie disease. Progressive hearing loss starts in early childhood for a majority of males with the disease. Early hearing loss is sensorineural, mild and asymmetric. By adolescence, high-frequency hearing loss begins to appear. Hearing loss is severe, symmetric, and broad-spectrum by the age of 35. However, studies show that while the hearing loss is deteriorating, the ability to speak well is highly preserved. The slowly progressing hearing loss is more problematic in adjusting to than the congenital blindness for most people with Norrie disease

-X linked recessive -mutation in ATP7A gene => inadequate distribution of copper in cells => accumulation of copper in some areas (small intestine, kidneys), low levels of copper in other areas (brain) -present at 2-3 months with loss of developmental milestones, truncal hypotonia, epilepsy, failure to thrive -brittle, sparse, kinky hair/eyebrows/eyelashes, connective tissue abnormalities (loose skin, joint hypermobility), vascular defects (arterial rupture, aneurysms, thrombosis), skeletal changes (fractures, osteoporosis), sagging facial features -screening: urine homovanillic acid/vanillylmandelic acid ratio -imaging: white matter demyelination, tortuous blood vessels, atrophy, SDH -treatment: supportive; copper supplementation copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency. It is an x-linked recessive disorder, and is therefore considerably more common in males: females require two defective alleles to develop the disease. MNK is characterized by sparse and coarse hair, growth failure, and deterioration of the nervous system. Onset of Menkes syndrome typically begins during infancy. Signs and symptoms of this disorder include weak muscle tone (hypotonia), sagging facial features, seizures, mental retardation, and developmental delay. The patients have brittle hair and metaphyseal widening. In rare cases, symptoms begin later in childhood and are less severe. Affected infants may be born prematurely. Symptoms appear during infancy and are largely a result of abnormal intestinal copper absorption with secondary deficiency in copper-dependent mitochondrial enzymes. Normal or slightly slowed development may proceed for 2 to 3 months, and then there will be severe developmental delay and a loss of early developmental skills. Menkes Disease is also characterized by seizures, failure to thrive, subnormal body temperature, and strikingly peculiar hair, which is kinky, colorless or steel-colored, and easily broken. There can be extensive neurodegeneration in the gray matter of the brain. Arteries in the brain can also be twisted with frayed and split inner walls. This can lead to rupture or blockage of the arteries. Weakened bones (osteoporosis) may result in fractures. Occipital horn syndrome (sometimes called X-linked cutis laxa or Ehlers-Danlos type 9), is a mild form of Menkes syndrome that begins in early to middle childhood. It is characterized by calcium deposits in a bone at the base of the skull (occipital bone), coarse hair, and loose skin and joints. Mutations in the ATP7A gene, located on chromosome Xq12-q13, are the cause of Menkes syndrome. As the result of a mutation in the ATP7A gene, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels and the nervous system such as lysyl oxidase. This condition is inherited in an X-linked recessive pattern. Diagnose with urine homovanillic acid/vanillylmandelic acid which is elevated. Early treatment with subcutaneous or intravenous injections of copper supplements (in the form of acetate salts) may be of some benefit. Other treatment is symptomatic and supportive

1X (CMT1X) is the second most common cause of CMT, caused by mutations in the gap junction beta 1 (GJB1) gene encoding the protein connexin 32 (Cx32). Cx32 is part of a large family of highly conserved proteins that form gap junctions to allow for movement of small molecules and ions between cells. Cx32 is expressed by Schwann cells in the peripheral nervous system (PNS), most likely forming gap junctions between layers of the myelin sheath [5]. Cx32 is also expressed by oligodendrocytes in the central nervous system (CNS), coupling oligodendrocytes and astrocytes [6]. Impairment in CMT1X appears to be caused by loss of function [7], and typically arises solely from PNS dysfunction. However, there have been several case reports of people with abnormal brainstem auditory evoked responses (BAER) and reports describing transient CNS dysfunction with associated magnetic resonance imaging (MRI) changes in people with CMT1X.. These comprise a well recognized transient CNS phenotype that includes dysarthria, ataxia, and white matter changes seen on MRI, not characteristic of demyelination. Charcot-Marie-Tooth Disease (CMTX) connexin 32 Form X 1. Severe Acid Reflex as an infant 2. Crying and moaning as an infant 3. Nystagmus 4. Poor Balance 5. Truncal ataxia 6. Tremors 7. Stroke like symptoms 8. Delayed speech 9. Paresthesias approximately 15% of individuals with CMT have a form of the disorder linked to the X chromosome (called CMTX). Studies have shown that individuals with CMTX may have transient central nervous system symptoms in addition to the more common symptoms.

X-linked sideroblastic anemia and ataxia is a rare condition characterized by sideroblastic anemia and ataxia. This condition occurs only in males. Sideroblastic anemia results erythroblasts do not make enough hemoglobin. People with X-linked sideroblastic anemia and ataxia have a microcytic, hypochromic anemia. This disorder also leads to an abnormal accumulation of iron in red blood cells. The iron-loaded erythroblasts, which are present in bone marrow, are called ring sideroblasts. Unlike other forms of sideroblastic anemia, X-linked sideroblastic anemia and ataxia does not cause a potentially dangerous buildup of iron in the body. The anemia is typically mild and usually does not cause any symptoms. X-linked sideroblastic anemia and ataxia causes problems with balance and coordination that appear early in life. The ataxia primarily affects the trunk, making it difficult to sit, stand, and walk unassisted. In addition to ataxia, people with this condition often have trouble coordinating movements that involve judging distance or scale (dysmetria) and find it difficult to make rapid, alternating movements (dysdiadochokinesis). Mild speech difficulties (dysarthria), tremor, and abnormal eye movements have also been reported in some affected individuals. Mutations in the ABCB7 gene cause X-linked sideroblastic anemia and ataxia. The ABCB7 gene provides instructions for making a protein that is critical for heme production. The ABCB7 protein also plays a role in the formation of certain proteins containing clusters of iron and sulfur atoms. Overall, researchers believe that the ABCB7 protein helps maintain an appropriate balance of iron (iron homeostasis) in developing red blood cells. ABCB7 mutations slightly alter the structure of the ABCB7 protein, disrupting its usual role in heme production and iron homeostasis. Anemia results when heme cannot be produced normally, and therefore not enough hemoglobin is made. It is unclear how changes in the ABCB7 gene lead to ataxia and other problems with movement

The main feature is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. It is sometimes described as not affecting the sensory tracts, and sometimes described as affecting the sensory tracts late in the course. Conditions other than progressive spasticity may be present, but these are considered complications of the hereditary spastic paraplegia, and only the spastic paraplegia is inherently intrinsic to the condition. The major neuropathologic feature of HSP is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved and there is no evidence of primary demyelination. Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal. Average age of onset is 24 y/o. Spasticity in the lower limbs alone is described as pure HSP. On the other hand, HSP is classified as complex or complicated when associated with other neurological signs, including ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction or epilepsy, or with extraneurological signs. Complicated forms are diagnosed as HSPs when pyramidal signs are the predominant neurological characteristic. This classification, however, is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia, mental retardation or leukodystrophy. The main feature of the disease is progressive spasticity in the lower limbs, due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HPS are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.[14] Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses insidiously over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices. More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles. In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, mental retardation, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing. Although HSP is a progressive condition and usually starts in the legs and spreads to other muscles, ultimately leading to confinement to bed, the prognosis for individuals with HSP varies greatly. Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life. The majority of individuals with HSP have a normal life expectancy. X linked recessive inheritance shows abnormalities of two genes, SPG2 (proteolipid protein) and SPG1 (L1CAM - neuronal cell adhesion molecule L1). Mutations in the proteolipid protein cause cause progressive leukodystrophy and dysmyelination, resulting in axonal degeneration. Mutations in L1CAM interfere with its role in neurite outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts. Treatment consists of medical management of symptoms

X-linked dystonia-parkinsonism or Lubag (which is its Filipino name), this neurodegenerative disorder is transmitted as an X-linked recessive trait. It has primarily been reported in young adult males from the island of Panay in the Philippines. However, a few cases have been described in which females who carry a copy of the disease gene (heterozygous carriers) may manifest mild symptoms of the disorder, such as relatively mild dystonia or chorea. The mean age at onset is approximately 35 years, with 14 years the youngest reported age at onset. Symptoms may initially include focal dystonia of the neck; lower limbs; upper limbs; or trunk. Cranial involvement often affects muscles of the jaw, mouth, lower face, and tongue (oromandibular/lingual dystonia). In addition, in those with involvement of the vocal cords, symptoms may include an unusual, high-pitched sound upon inhalation (stridor). With disease progression, the dystonia usually becomes generalized. In some patients, signs of parkinsonism may accompany, precede, or "replace" symptoms of dystonia. Such findings may include stiffness (rigidity), slowness of movement (bradykinesia), a shuffling manner of walking (gait), and/or postural instability (although resting tremor is rarely present). Less commonly, patients may develop progressive parkinsonism as an isolated manifestation of the disorder. The gene for X-linked dystonia-parkinsonism (DYT3) has been mapped to chromosome Xq13.1. Neuroimaging studies may reveal neurodegenerative changes (e.g., gliosis and neuronal loss) within substructures of the basal ganglia (i.e., striatum). Parkinsonism symptoms may slightly improve with L-dopa or dopamine agonist therapy, and dystonic features may have only a partial response to anticholinergics or benzodiazepines, such as clonazepam

X-linked recessive retinal degenerative disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye. Choroideremia (CHM) is a rare inherited disorder that causes progressive loss of vision due to degeneration of the choroid and retina. It occurs almost exclusively in males. In childhood, night blindness is the most common first symptom. As the disease progresses, there is loss of vision, frequently starting as an irregular ring that gradually expands both in toward central vision and out toward the extreme periphery. Progression of the disease continues throughout the individual's life. Both the rate of change and the degree of visual loss are variable among those affected, even within the same family. The actual vision loss is caused by degeneration of several layers of cells that are essential to sight. These layers, which line the inside of the back of the eye, are called the choroid, the retinal pigment epithelium (RPE), and the retina. The choroid is a network of blood vessels located between the retina and the sclera, the "white of the eye." Choroidal vessels provide oxygen and nutrients to both the RPE and the retina's photoreceptor cells. The RPE, directly beneath the retina, supports the function of photoreceptor cells. Photoreceptors convert light into the electrical impulses that transfer messages to the brain where "seeing" actually occurs. In the early stages of Choroideremia, the choroid and the retinal pigment epithelium initially deteriorate. Eventually, photoreceptor cells also degenerate. As a result, vision is lost. Choroideremia is caused by the deletion of the Rab escort protein 1 (REP1). Rab escort protein 2 (REP2) is 75% identical and can almost compensate for the loss of REP1. Though the eye does express the REP2 protein (no cell could survive without some REP activity) evidently, in the eye, this is not enough. The REPs are essential for the prenylation of Rab proteins. Studies have shown that there is a build up of unprenylated Rab27 in lymphoblasts from Choroideremia patients. The link between the build up of unprenylated Rabs and blindness is not known. Generally, only men show symptoms of this disease, although in rare cases some women also acquire it. Initially a person suffering from choroideremia has night blindness, which begins in youth. As the disease progresses, a CHM sufferer loses their peripheral vision and depth perception, eventually losing all sight by middle age. In some cases, a severe loss of acuity and color perception become evident as the disease progresses.

X-linked spinal and bulbar muscular atrophy (SBMA) or spinobulbar muscular atrophy or X-Linked bulbo-spinal atrophy is a neuromuscular disease associated with mutation of the androgen receptor (AR). Because of its endocrine manifestations related to the impairment of the AR, it can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). The androgen receptor gene that is mutated in Kennedy's disease is located on the X chromosome, and the effects of the mutation may be androgen-dependent, thus only males are fully affected. Females are rarely affected; female carriers tend to have a relatively mild expression of the disease if they show symptoms at all. Kennedy's disease is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene (trinucleotide repeats). The CAG repeat encodes a polyglutamine tract in the androgen receptor protein. The greater the expansion of the CAG repeat, the earlier the disease onset and more severe the disease manifestations. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration. KD may share mechanistic features with other disorders that are caused by polyglutamine expansion, such as Huntington's disease. There is currently no treatment or cure for Kennedy's disease. It is a lower motor neuron disease. patients have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. The latest onset was described in a male of 84 years of age. KD does not usually compromise longevity. The syndrome has neuromuscular and endocrine manifestations. Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. In some cases, premature muscle fatigue begins in adolescence. Neuromuscular management is supportive, and the disease progresses very slowly and often does not lead to extreme disability. Neurological: • Bulbar signs • Lower motor neuron signs • Primary sensory neuropathy • Intention tremor: • Babinski (plantar) response • Decreased or absent deep tendon reflexes Muscular: • Fasciculations • Cramps • Muscular atrophy Endocrine • Gynecomastia • Impotence • Erectile dysfunction • Reduced fertility • Low sperm count • Testicular atrophy Miscellaneous Characteristics: • Late onset: Patients usually develop symptoms in the late 30's or later • Symmetry of clinical signs: Muscles are usually affected symmetrically. Homozygous females, both of whose X chromosomes have a mutation leading to CAG expansion of the AR gene, have been reported to show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described

angiokeratoma corporis diffusum and alpha-galactosidase A deficiency) is a rare X-linked recessive (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms. A deficiency of the enzyme alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper function. The condition affects hemizygous males (i.e. all males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. This variability is thought to be due to X-inactivation patterns during embryonic development of the female. Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages. Pain management Daily prophylactic doses of neuropathic pain agents (eg, phenytoin, carbamazepine, gabapentin, or a combination of these agents) provide some degree of relief. They are effective in decreasing the frequency and severity of pain episodes or pain crises in most patients. Some patients may require more potent analgesics (eg, opioids) for pain management. Renal involvement Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure may worsen throughout life. Proteinuria is often the first sign of kidney involvement. End stage renal failure in males can typically occur in the third decade of life, and is a common cause of death due to the disease. Cardiac manifestations Cardiac complications occur when glycolipids build up in different heart cells; heart related effects worsen with age and may lead to increased risk of heart disease. Hypertension (high blood pressure) and cardiomyopathy are commonly observed. Dermatological manifestations Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the belly-button, buttocks, lower abdomen, and groin) are a common symptom. Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating). Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain). Ocular manifestations Cosmetic ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic carriers, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision. Other ocular findings that can be seen include conjunctival aneurysms, posterior spoke-like cataracts, papilloedema, macular edema, optic atrophy and retinal vascular dilation. Other manifestations; Fatigue, neuropathy, cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, and diarrhea are other common ymptoms. Fabry disease is indicated when associated symptoms are present, and can be diagnosed by a blood test to measure the level of alpha-galactosidase activity, however this may be misleading in female carriers due to the random nature of X-inactivation. Chromosomal analysis of the GLA gene is the most accurate method of diagnosis, and many mutations which cause the disease have been noted. Kidney biopsy may also be suggestive of Fabry Disease if excessive lipid buildup is noted. Naturally, alpha-galactosidase A (a-GAL A) is likely to be present only at very low levels in the blood, particularly in males. In females, owing to X-inactivation patterns, levels are commonly normal even if the patient is not asymptomatic. The Sifap (stroke in young Fabry patients) project will investigate the relation between stroke and Fabry's disease. Until the 2000s, treatment of Fabry disease targeted the symptomatic effects. In 2001, three Enzyme Replacement Therapies (ERTs) were released: Agalsidase alpha (Replagal, manufactured by Shire) and Agalsidase beta (Fabrazyme, manufactured by Genzyme). These attempt to replace the deficient enzyme by means of infusion, most commonly, every two weeks. The cost of these drugs is problematic (approximately $250,000 US a year/patient) and remains a barrier to many patients in some countries. The infusion may be performed by the patient themselves, in the patient's home by a registered nurse, or at a medical facility. Enzyme replacement therapy is not a cure, but can allow normal metabolism and both prevent disease progression as well as potentially reverse symptoms.

coordination, motor abilities, and intellectual function are delayed to variable extents. X linked recessive inheritance pattern. PLP1 gene on X chromosome (Xq22.2) or point mutations. PLP1 encodes compact myelin proteins PLP1 and DM20. There is absence of or reduced myelin sheaths in white matter (especially periventricular) with relative preservation of axons. There are patchy areas of residual myelin islets with a "tigroid" pattern, marked astrocytosis, sparing of subcortical U fivers and sparing of fibers in peripheral nerves (includes cranial nerves). Clinical features show at 3 months, delayed motor milestones, hypotonia, nystagmus. By 6-18 months, patients can get ataxia and other movement d/o such as choreathetosis. By 4 years, develop spasticity. Despite symptoms, motor development continues slowly and reaches a plateau in the 2nd decade of life followed by psychomotor deterioration. On MRI there is lack of normal high T1 signal of white matter, no clear demarcation b/w white and gray matter, persitently hight T2 signal present diffusely in white matter (sparing U fibers) and no change on repeated MRIs despite clinical progression.

X-linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities. The syndrome is caused by mutations in the RPS6KA3 gene. This gene is located on the short arm of the X chromosome (Xp22.2). The RPS6KA3 gene makes a protein that is involved with signaling within cells. Researchers believe that this protein helps control the activity of other genes and plays an important role in the brain. The protein is involved in cell signaling pathways that are required for learning, the formation of long-term memories, and the survival of nerve cells. The protein RSK2 which is encoded by the RPS6KA3 gene is a kinase which phosphorylates some substrates like CREB and histone H3. RSK2 is involved at the distal end of the Ras/MAPK signaling pathway. Mutations in the RPS6KA3 disturb the function of the protein, but it is unclear how a lack of this protein causes the signs and symptoms of Coffin-Lowry syndrome. At this time more than 120 mutations have been found1. Some people with the features of Coffin-Lowry syndrome do not have identified mutations in the RPS6KA3 gene. Coffin-Lowry syndrome is a severe mental retardation associated with abnormalities of: In utero growth is normal but post natal growth is retarded. Patients are sometimes microcephalic. Cardiac abnormalities affect 15% of the patients. Progressive kyphoscoliosis affects 1 in 2 patients. Micrognathia is also associated with this syndrome. Patients may also have an underdeveloped upper jaw bone, abnormally prominent brows, or widely spaced eyes. Auditory abnormalities are frequent and often present. Vision abnormalities are not often present

Disease characteristics. LIS1-associated lissencephaly/subcortical band heterotopia (SBH) includes Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS). Lissencephaly and SBH are cortical malformations caused by deficient neuronal migration during embryogenesis. Lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). SBH refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. MDS is characterized by lissencephaly, typical facial features, and severe neurologic abnormalities. ILS is characterized by lissencephaly and its direct sequelae: developmental delay, mental retardation, and seizures. Diagnosis/testing. MDS is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include LIS1 (also known as PAFAH1B1) and additional telomeric genes. ILS is caused by smaller submicroscopic deletions of LIS1; intragenic deletions or duplications of LIS1; or sequence variants of LIS1. Cytogenetic testing, FISH testing, deletion testing, and sequence analysis of LIS1 are available clinically. Management. Treatment of manifestations: Poor feeding may require nasogastric tube feedings in newborns and later placement of a gastrostomy. Seizures require prompt and aggressive management based on the specific seizure type and frequency; response to treatment is similar to that in children with seizures due to other causes. Genetic counseling. Approximately 80% of individuals with MDS have a de novo deletion involving 17p13.3 and approximately 20% have inherited a deletion from a parent who carries a balanced chromosome rearrangement. If neither parent has a structural chromosome rearrangement detectable by high-resolution chromosome analysis, the risk to sibs is negligible. If a parent has a balanced structural chromosome rearrangement, the risk to sibs for MDS depends on the specific rearrangement. Although mosaicism in a parent could lead to familial recurrence of ILS, all LIS1 intragenic mutations reported to date have been de novo; thus, the risk to sibs for ILS is negligible if neither parent has mosaicism for the LIS1 mutation present in the proband. Prenatal testing for pregnancies at increased risk for MDS is possible if the familial chromosome rearrangement is known

X-linked recessive disorder characterized by hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria, reduced renal ammonia production and vitamin D-resistant rickets. Boys with Lowe Syndrome are born with cataracts in both eyes, which are usually removed at a few months of age. Most boys are fitted with glasses, contact lenses, or a combination of the two. Glaucoma is present in about 50% of the boys with Lowe syndrome, though usually not at birth. Prescription eye drop and/or surgery is required to maintain appropriate eye pressure in these cases. While not present at birth, many Lowe Syndrome boys develop kidney problems at approximately one year of age. This is characterized by the abnormal loss of certain substances into the urine, including bicarbonate, sodium, potassium, amino acids, organic acids, albumin and other small proteins, calcium, phosphate, glucose, and L-carnitine. This problem is known as Fanconi-type renal tubular dysfunction and can also be seen in certain other diseases and syndromes. In Lowe syndrome, the Fanconi syndrome may be mild and involve only a few substances or may be severe and involve large losses of many substances. Medications can be prescribed to replace the lost substances. Lowe syndrome is a "genetic" condition (i.e. occurs from birth, due to a gene mutation that may not have any family history, or may be hereditary) and affects mainly males. It is caused by a single defective gene (an alteration or "mutation") in a gene called OCRL1. Because of this defective gene, an essential enzyme called PIP2-5-phosphatase is not produced. This is the underlying cause of Lowe syndrome. The gene has been mapped and the deficient enzyme has been identified, although its role is not fully understood. Today there is no correlation between the gene mutation, the level of enzyme deficienty and the symptoms. Other Syndromes such as Dents, may have almost identical mutations but while exhibiting some symptoms such as kidney disorders, do not have the enzyme deficiency or other symptoms such as cataracts

THE MARFANS MASQUERADER -autosomal recessive -deficiency of cystathionine synthase (classic form) or insufficient vitamin B12 synthesis or deficiency in methylenetetrahydrofolate reductase leading to defect in methionine metabolism -results in accumulation of methionine and homocysteine in serum and increased excretion of homocysteine in urine (level excreted in urine is greater than 200 mg) -neuro findings: developmental delay by age 2-3, seizures, muscular hypotonia -other findings: (similar to Marfans): tall, thin, long limbs, pectus excavatum, subluxation of lens (ectopic lentis), myopia, extensive atheroma formation, intravascular thrombosis, psychiatric symptoms, pale skin -brain MRI findings: may see basal ganglia, or supratentorial white matter abnormalities , hydrocephalus -approx ¼ of patients die as a result of thrombotic complications before age of 30 -Rx: high doses of vitamin B6, low protein (low methionine) diet, cysteine supplement, folic acid

-autosomal recessive, higher prevalence in Amish, Mennonite, Jewish descent -deficiency of branched chain alpha keto acid dehydrogenase complex (BCKDC) -accumulation of branched chain AA's (leucine, isoleucine, valine) -leucine causes the neuro symptoms => transported across BBB and metabolized to glutamate & glutamine -isoleucine => maple syrup odor -neuro findings: alternating hypotonia/hypertonia, dystonia, seizures, opisthotonus, encephalopathy -other findings: vomiting, dehydration, lethargy, ketoacidosis, pancreatitis -Rx: for episodes of acute metabolic decompensation, treat w/ IV glucose. Long-term: restrict intake of branched chain AA's.

-autosomal recessive, alpha subunit on chromosome 15, higher prevalence in Ashkenazi Jewish descent -hexosaminidase A deficiency, normally catalyzes degradation of FA derivatives (gangliosides) -accumulation of lipids in the brain -infantile: normal at birth, sx onset at 4-8 months, usual fatal by age 2-4 -Neuro Findings: "cherry red" macula => normal retina with surrounding gangliosides in retinal ganglion cells, MR, hyperreflexia, decreased tone (floppy), exaggerated startle response -Hepatosplenomegaly NOT a finding in this disease

beta subunit, also hexosB deficiency) TWIN OF TAY SACHS -autosomal recessive, beta subunit of chromosome 5 -mutation of HEXB gene => beta-hexosaminidase A & B DEFICIENY => normally breaks down gangliosides => accumulation of lipids -normal at birth, onset ~ 3-6 months, death before age 3 -Neuro Findings (essentially clinically indeterminable from Tay Sachs): developmental delay, loss of motor skills, MR, seizures, paralysis, myoclonus, macrocephaly Other findings: "cherry red" macula, HEPATOSPLENOMEGALY

-autosomal recessive -deficiency of arylsulfatase A => buildup of sulfatides => destruction of myelin -infantile form: age 4 or younger, death 5 years after symptoms begin -early juvenile form: age 4-6, death before age 20 -late juvenile form: 6-16 and survive into early adulthood -Neuro findings: loss of developmental milestones, tremor, truncal ataxia, hypperreflexia progressing to hyporeflexia, hypotonia, gait abnormalities, optic atrophy, memory loss, personality changes -Brain MRI: white matter abnormalities and atrophy -Histology: metachromatic granules in peripheral nerves, kidney, gallbladder -Rx: supportive, bone marrow transplant may stabilize neurocognitive function in late juvenile/adult forms

-autosomal recessive, chromosome 11, higher prevalence in Ashkenazi Jewish descent -missense mutation causing sphingomyelinase deficiency => blocks degradation of lipid => accumulation of sphinogmyelin within lysosomes -type A: is results in death by age 2-3, type B is milder with later onset/longer survival with no neuro sx Neuro findings: dysarthria, dystonia, gait disturbance, loss of motor function leading to spasticity, supranuclear gaze palsy -Other findings: failure to thrive , "cherry red" macula, hepatosplenomegaly, pancytopenia -Histology: lipid laden foam cells on bone marrow examination

-autosomal recessive on chromosome 6 -sialidase deficiency => accumulation of complex carbs (mucopolysaccarides) and mucolipids -Neuro findings: macrocephaly, hypotonia, visual impairment, myoclonic seizures, MR -Other findings: excessive swelling throughout the body, "cherry red" macula, course facial features, skeletal malformations, hepatosplenomegaly -histology: cytoplasmic vacuolation in peripheral lymphocytes

-autosomal recessive on chromosome 1, higher prevalence in Ashkenazi Jewish descent -deficiency of glucocerebrocidase (aka beta-glucosidase) => accumulation of glucocerebrocide -Type 1 (non-neuro): HSM, pancytopenia, skeletal (lytic lesions, frx, osteoporosis) -Type 2 (infantile neuropathic): present within 6 months of birth with increased tone, seizures, MR, apnea, strabismus, HSM, progressive psychomotor degeneration. Death by age 2 -Type 3 (chronic neuropathic): , myoclonus, slowing of horizontal saccades/ocular motor apraxia Live into early teen years/adulthood. -histology: Gaucher cells - "wrinkled paper" appearance, periodic Acid Sshiff (+) -Rx: Enzyme Replacement, i.e. Imiglucerase (IV recombinant beta-glucocerebrocidase), BM transplant

-autosomal recessive on chromosome 14 -deficiency of galactosylceramide beta galactosidase (GALC) which is highly concentrated in myelin sheath and degrades galactosylceramide => deficiency of galactocerebrosidase -accumulation of galactocerebroside => destruction of oligodendroglia and Schwann cells (myelin is qualitatively normal) -symptoms begin at 3-6 months, death before age 2 -Stage 1: irritability, hypertonia, hyperesthesia (auditory/visual/tactile), psychomotor arrest, FTT -Stage 2: hypertonia, seizures, opisthotonus, optic atrophy, visual loss -Stage 3: blindness, deafness, decerebrate posturing -Imaging: Diffuse symmetric cerebral atrophy of grey & white matter, demyelination of brainstem & cerebellum -Histology: globoid cells (multinucleated macrophages with abundant cytoplasm that cluster around blood vessels), white matter shows gliosis, demyelization, decreased oligodendrioglial cells

-autosomal recessive on chromosome 4 -deficiency of alpha-L iduronidase (degrades mucopolysaccharides in lysosomes) -buildup of glycosaminoglycan (heparan sulfate & dermatan sulfate) -death before age 10 -Neuro findings: developmental delay, MR, carpal tunnel syndrome -Other findings: coarse facial features, corneal clouding, HSM, dwarfism, hearing loss, skeletal, aortic valve dz, joint stiffness -Rx: supportive, Enzyme Replacement w/ Laronidase, recombinant alpha-L iduronidase

-autosomal recessive -deficiency of one of four enzymes that degrade heparin sulfate: 1. heparan sulfate sulfatase, 2. N-acetyl-alpha-D glucosaminidase (NAG), 3. Acetyl-CoA: alpha-glucosamide acetyltransferase, 4. N-acetylglucosamine-6-sulfatase -accumulation of heparan sulfate w/ increased urinary excretion -normal at birth, onset of symptoms occurs at 2-6 years old -Findings: hyperactivity, agression, OSA, speech deficits, course facial & body hair, skeletal, hearing loss -Imaging: obstructive hydrocephalus (obstruction of foramina of Luschka & Magendie)

-sporadic inheritance -spontaneous mutation in gene that encodes glial fibrillary acidic protein (GFAP) on chromosome 17 -formation of Rosenthal fibers in astrocytes -Infantile form: most common, onset during first 2 years of life, pass away within 10 years of sx onset -Neuro findings: macrocephaly, seizures, MR, spastic quadriparesis, hydrocephalus -juvenile form: onset begins at 2 - 13 years of age, get vomiting, difficulty swallowing, poor coordination, loss of motor control, sleep disturbance -adult form: rare, symptoms can mimick MS or Parkinson's

-autosomal recessive -mutation in mitochondrial or nuclear DNA => gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem. -age of onset: 2 months - 3 years. Life expectancy: within a year of onset of sx -Neuro findings: developmental delay, irritiability, seizures, hypotonic, opthalmoplegia, ataxia, pyramidal and extra pyramidal signs,, lactic acidosis -X linked form: mutation in mutation of gene encoding PDHA1, part of pyruvate dehydrogenase complex => pyruvate dehydrogenase deficiency -treatment: supportive; thiamine and vitamin B1

-autosomal recessive -genetic mutation of POLG gene that codes for catalytic subunit of mitochondrial DNA polymerase => depletion of mitochondrial DNA => progressive degeneration of grey matter -intractable seizures (may have epilepsia partialis continua), developmental delay/mental retardation, hypotonia, spasticity, optic atrophy, deafness, jaundice, liver failure -pathology: status spongiosus of grey matter -poor prognosis, death within first decade of life -treatment: supportive, avoid valproate to treat seizures as this can increase risk of liver failure

-X-linked recessive -mutation in HPRT1 gene => deficiency of HGPRT => uric acid overproduction -present 3-12 years old Neuro findings: delayed motor development, self-injurious behavior resulting in amputations , compulsive behavior, impaired cognitive function, pyramidal sx, extrapyramidal sx (esp generalized dystonia), Other findings: testicular atrophy, increased risk for kidney stones and gout, macrocytic anemia Treatment: for hyperuricemia: allopurinol and hydration.

-autosomal dominant, variable penetrance -mutation of TSC1 (encodes for hamartin) on chromosome 9 or TSC2 (encodes for tuberin) on chromosome 16 which are tumor growth suppressors Major features -Facial angiofibromas or forehead plaque -Nontraumatic ungual or periungual fibroma -Hypomelanotic macules (>3) -Shagreen patch (connective tissue nevus) -Multiple retinal nodular hamartoma -Cortical tuber: When cerebellar cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis. -Subependymal nodule -Subependymal giant cell astrocytoma -Cardiac rhabdomyoma, single or multiple -Lymphangioleiomyomatosis: -Renal AML: -Tubers are noted most commonly in the cerebrum, without clear predilection for any particular lobe. -Neuro symptoms depend tuber location: abnormalities in cognition, cranial nerves, focal motor/sensory/reflexes abnormalities, cerebellar dysfunction, or gait abnormalities. -Rx: supportive, Rapamune (sirolimus, an immunosuppressant that inhibits T cell proliferation)

-autosomal dominant, mutation or deletion of NF1 gene on chromosome 17 -Gene product: neurofibromin (inhibit ras activity) => decreased inhibition of cell proliferation Two of these seven "Cardinal Clinical Features" are required for positive diagnosis -6 or more café-au-lait macules over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals -2 or more neurofibromas of any type or 1 plexiform neurofibroma -Freckling in the axillary or inguinal regions -Optic glioma -2 or more Lisch nodules (iris hamartomas) -A distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis -A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria -In addition, patient may have -Chronic pain, and numbness due to the peripheral nerve sheath tumors , Blindness from optic nerve gliomas, chronic hypertension or pheochromocytomas -Brain MRI will show unidentified bright objects (UBOs) that don't enhance or cause mass effect -Rx: removal of neurofibromas, symptomatic treatment

- Autosomal dominant, NF-2 gene on chromosome 22 -gene product: merlin ( a tumor suppressor) -presenting symptoms: hearing loss, tinnitus, balance problems/disequilibrium, headache, abnormal corneal reflex, nystagmus -Neuro Findings: bilateral acoustic neuromas, cranial nerve tumors causing CN palsies, spinal astrocytomas or ependymomas (intramedullary), spinal schwannomas and meningiomas (extramedullary), sup capsular cataracts in juveniles -can develop multiple subcutaneous lesions (neurilemomas or schwannomas) -Rx: surgical resection of clinically significant tumors, chemo and radiation may serve palliative function

occurring before age 65 yrs old age. Due to presenillin 1 on chr 14. Approximately half the cases of early-onset Alzheimer's are Familial.

characterized by slowly progressive clumsiness and weakness in the arms and legs, spasticity, a staggering lurching gait easily mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, double vision, and frequent urination. Some individuals also have dystonia (sustained muscle contractions that cause twisting of the body and limbs, repetitive movements, abnormal postures, and rigidity) or symptoms similar to those of Parkinson's disease. Others have twitching of the face or tongue, or peculiar bulging eyes. Almost all individuals with MJD experience vision problems, including double vision or blurred vision, loss of the ability to distinguish color and/or contrast, and inability to control eye movements. MJD is incurable, but some symptoms of the disease can be treated. For those individuals who show parkinsonian features, levodopa therapy can help for many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity as well as some symptoms of dystonia. Speech problems and trouble swallowing can be treated with medication and speech therapy.

usually manifests itself during early childhood at around ages 5-8 years. typically absent in the morning or after rest but worsening during the day and with exertion. Children with DRD are often misdiagnosed as having cerebral palsy. The disorder responds well to treatment with levodopa. Autosomal dominant and autosomal recessive forms of the disease have been reported. Mutations in several genes have been shown to cause dopamine-responsive dystonia.

Variegate porphyria (VP, porphyria variegata, protocoproporphyria, South African genetic porphyria) is an autosomal dominant type of hepatic porphyria, resulting from deficient activity of protoporphyrinogen oxidase (PPO). The disease was termed "variegate" because it can present with neurologic manifestations, cutaneous photosensitivity, or often both. Some cases of VP were described as having "porphyria cutanea tarda hereditaria", before VP and PCT were clearly distinguished, while the term "mixed porphyria" referred to either hereditary coproporphyria (HCP) or VP. This disorder has also been termed the "Royal Malady", based on the suggestion that some British royalty may have had this condition. Abnormally high levels of the porphyrin precursors porphobilinogen and aminolevulinic acid are found during episodic attacks of systemic symptoms. These episodes are caused by dysfunctions of central, autonomic, and peripheral nervous systems that appear to be effects of deranged heme synthesis on neurons

AD; 60s. PABPN1 gene (Polyadenylate-binding protein 2). Progressive ptosis and weakness of the extraocular muscles is the initial clinical finding which continues until paralysis of all eye movements occurs; however, pupillary reactions remain unaffected. Dysphagia , facial weakness and proximal limb weakness develops later on in the disease. A muscle biopsy reveals abnormal vacuoles within muscle fibres. A distinction between OPD and myasthenia gravis or mitochondrial myopathy must be made. The absence of family history and the fluctuation of symptoms in myasthenia gravis usually distinguish the two conditions.

caused by deletion or inactivation of genes on the maternally inherited chromosome 15. characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanor.

loss of paternally inherited genes and maternal imprinting.

• LGMD2A (calpainopathy) o LGMD2A is likely the most common autosomal recessive LGMD, accounting for up to 30% of all cases. In some areas, including the Basque region of Spain (where a founder mutation is identified), LGMD2A accounts for almost 80% of all cases of LGMD. In other areas, it is quite rare; for example, it accounts for only 6% of LGMD cases in Denmark. o About two thirds of patients present at 8-15 years of age, with a range of 2-40 years. o The most typical presentation is of weakness due to scapular-humeral-pelvic weakness that may be similar to the presentation of facioscapulohumeral dystrophy, but without facial weakness. LGMD2I may also have a similar phenotype. o Hip-girdle weakness is most prominent in the gluteus maximus and hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait. o The combination of scapular winging, severe weakness of hip adductors and elbow flexors, normal respiratory function, and contractures has specificity for LGMD2A.7 o Atrophy is often prominent. o Progression tends to be slow, and wheelchair use begins 11-28 years after the onset of symptoms. o The clinical course varies widely among and within families. o Atypical presentations include a severe Duchenne-like course, exercise-induced stiffness and myalgia before the onset of weakness, and early and clinically significant contractures (especially of the ankles, elbow, and neck) similar to those of Emery-Dreifuss muscular dystrophy. o Presentation with asymptomatic hyperCKemia has been reported in up to 10% of cases. o Facial and cardiac involvement have not been reported.

Peripheral neuropathy; areflexia, hypotonia. muscle wasting (amyotrophy), severe progressive weakness and loss of sensation in the limbs, and rhythmic shaking (tremors). They typically begin walking between ages 3 and 4 and lose this ability by their teenage years. As they get older, people with this disorder frequently develop joint deformities called contractures, which restrict the movement of certain joints. Most affected individuals also develop abnormal curvature of the spine (scoliosis), which may require surgery. Andermann syndrome also results in abnormal function of certain cranial nerves, which emerge directly from the brain and extend to various areas of the head and neck. Cranial nerve problems may result in facial muscle weakness, drooping eyelids (ptosis), and difficulty following movements with the eyes (gaze palsy). Mutations in the SLC12A6 gene cause Andermann syndrome. The SLC12A6 gene provides instructions for making a protein called a K-Cl cotransporter.

characterized mainly by convulsions during infancy and choreoathetosis which can occur randomly or be triggered by certain stimuli such as exercise. Benign infantile convulsions and paroxysmal dyskinesia are episodic cerebral disorders that can share common genetic bases. They can be co-inherited as one single autosomal dominant trait (ICCA syndrome); the disease ICCA gene maps at chromosome 16p12-q12. Despite intensive and conventional mutation screening, the ICCA gene remains unknown to date.

excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the technical word lipo, which is a variation on "lipid" or fat, and from the term pigment, used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys

pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The main clinical features are rod-cone dystrophy, with childhood-onset visual loss preceded by night blindness; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; specific learning difficulties; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of secondary features that are sometimes associated with BBS"[2] including[3] • Speech disorder/delay • Strabismus/cataracts/astigmatism • "Brachydactyly/syndactyly of both the hands and feet is common, as is partial syndactyl (most usually between the second and third toes)" • "Developmental delay: Many children with BBS are delayed in reaching major developmental milestones including gross motor skills, fine motor skills, and psychosocial skills (interactive play/ability to recognize social cues)" • Polyuria/polydipsia (nephrogenic diabetes insipidus) • Ataxia/poor coordination/imbalance • Mild hypertonia (especially lower limbs) • Diabetes mellitus • Dental crowding/hypodontia/small dental roots; high-arched palate • Cardiovascular anomalies • Hepatic involvement • Anosmia • Auditory deficiencies • Hirschsprung disease The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body and cilia of the cell.

'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). SCA4 is characterized by a spinocerebellar ataxia with sensory axonal neuropathy is on chromosome 16. It is due to CAG repeat and the defect gene is PLEKHG4). This disease typically present between 4th -7th decades and most patients experience areflexia.

slowly progressive disorder and causes loss of night vision (nyctalopia) and peripheral visual field in adolescence. It can be inherited through an autosomal dominant, recessive, or X-linked mode; the autosomal dominant form is considered to be the mildest form. Cones affected before rods. • RP combined with deafness = Usher syndrome. Leading cause of deafblindness • RP combined with opthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns-Sayre syndrome (aka Ragged Red Fiber Myopathy) • RP combined with retardation, peripheral neuropathy, acanthotic (spiked) RBCs, ataxia, steatorrhea, is absence of VLDL is seen in abetalipoproteinemia. • Other conditions: neurosyphilis, toxoplasmosis. abetalipoproteinemia, and Refsum's disease.

Physiologic/Genetic Abnormality: AUTOSOMAL DOMINANT. Peripherin 2 (aka peripherin/RDS or RDS) is a cell surface glycoprotein found on rod and cone photoreceptor cells. Responsible for initiation of visual phototransduction upon reception of light. Essential for disk morphogenesis. Defects are associated with central and peripheral retinal degeneration.

Clinical: Congenital muscular dystrophies (CMD) are a group of neuromuscular disorders with severe muscle hypotonia at birth or within the first months of life, generalised muscle weakness, contractures of variable severity and delayed motor milestones. Physiologic/Genetic Abnormality: The α2 chain of laminin-2 (merosin), encoded by a gene on chromosome 6q22, is deficient in about half the cases of congenital muscular dystrophy. Diagnosis of this condition has relied on immunocytochemical analysis of the α2 chain in muscle biopsy specimens. Histological changes in muscle biopsies consist of marked connective tissue proliferation, large variation in the size of the muscle fibres as well as some necrotic and regenerating fibres in early stages of the disease

Clinical: form of progressive myoclonus epilepsy beginning from age 6-19; characterized by generalized tonic-clonic seizures, resting and action myoclonus, ataxia, dementia, and classic EEG findings, including polyspike and wave discharges; basophilic cytoplasmic inclusion bodies present in portions of the brain, the liver, and skin, as well as the duct cells of the sweat glands. Death usually occurs within 10 years of onset. Genetic Abnormality: autosomal recessive inheritance, caused by mutation in the progressive myoclonic epilepsy 2 gene (EPM2A) on chromosome 6q

Muscle phosphoglycerate mutase deficiency results in a myopathic condition characterised by repeated cramps, possible myoglobinuria and exertional related muscle pain. Physiologic/Genetic Abnormality: Glycogenosis type X - Phosphoglycerate mutase deficiency; autosomal recessive (7p12-p13).