Other Hereditary Neuropathies




INTRODUCTION



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In Chapter 11, we reviewed Charcot–Marie–Tooth syndrome and related hereditary neuropathies. Here we discuss some of the more rare types of hereditary neuropathies (Table 12-1). Familial amyloid polyneuropathy is discussed in Chapter 16 (Neuropathies Associated with Systemic Disease).




TABLE 12-1.RARE HEREDITARY NEUROPATHIES




NEUROPATHIES ASSOCIATED WITH LYSOSOMAL STORAGE DISORDERS



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The lysosomal storage disorders are associated with abnormal accumulation of lysosomal products (e.g., sphingolipids, mucolipids, etc.) within neurons, leading to dysmyelination and axonal degeneration of both central and peripheral nerves (Table 12-1). Usually, the central nervous system (CNS) manifestations overshadow the peripheral neuropathy in most of these disorders. However, some patients present with peripheral neuropathy, which can be associated with significant disability.



METACHROMATIC LEUKODYSTROPHY



Clinical Features


There are three characteristic forms of metachromatic leukodystrophy (MLD) defined by age of onset: (1) late infantile, (2) juvenile, and (3) adult onset.114 Most patients have the late infantile–onset MLD variant and develop progressive generalized weakness, decline in mental functions, dysarthria, and worsening gait between 1 and 2 years of age. Children become quadriparetic, spastic, and cortically blind and often develop seizures. On examination, generalized muscle weakness, hypotonia, hyporeflexia, and extensor plantar responses are appreciated. Most children die within 5–6 years after onset of symptoms.



The juvenile form of MLD typically presents later in childhood or adolescence but is associated with clinical features similar to the late infantile form of the disease. Patients with adult-onset MLD usually develop slowly progressive dementia, psychosis, spasticity, ataxia, extrapyramidal signs, visual impairment, and incontinence in the third or fourth decade of life.15



Laboratory Features


Magnetic resonance imaging (MRI) of the brain often demonstrates increased signal on T2-weighted images in the subcortical white matter (Fig. 12-1).




Figure 12-1.


MRI of brain in a patient with MLD demonstrates widespread white matter disease on T2-weighted image. (Reproduced with permission from http://www.uiowa.edu/.)





The diagnosis is suggested by demonstrating decreased arylsulfatase A activity in urine, from leukocytes, or from cultured fibroblasts and can be confirmed with genetic testing. Prenatal diagnosis can be made by amniocentesis. Cerebral spinal fluid (CSF) protein is usually markedly elevated in the 100–300 mg/dL range. Motor nerve conduction studies (NCS) reveal mild to moderately reduced amplitudes, prolonged distal latencies, and marked slowing of conduction velocities (NCVs) that range from 10 to 20 m/s in the legs and 20 to 40 m/s in the arms.1,2,4,5,712,1517 Conduction block is not seen, but occasionally temporal dispersion is appreciated.11 Sensory NCS are often unobtainable, but when recordable the sensory nerve action potentials (SNAPs) are reduced in amplitude with slightly to moderately prolonged latencies and slow NCVs. Visual, brainstem, and somatosensory-evoked potentials are delayed.



Histopathology


Autopsy studies reveal degeneration of myelin in the CNS and peripheral nerves (Fig. 12-2).3,6,10,12 Nerve biopsies are not routinely performed but can also demonstrate a decrease in myelinated fibers with evidence of demyelination and remyelination (Fig. 12-3A). The characteristic abnormality is accumulation of metachromatically staining inclusions in cytoplasm of Schwann cells (Fig. 12-3B). On electron microscopy (EM), these inclusions appear as lamellated bodies within Schwann cells (Fig. 12-3C).




Figure 12-2.


MLD pathology. Lysosomal storage of sulfatides kills oligodendrocytes and Schwann cells. Sulfatides discharged from dying cells are picked up by histiocytes. The white matter shows diffuse loss of myelin, which spares the subcortical fibers. (Reproduced with permission from http://neuropathology-web.org/.)






Figure 12-3.


(A) Diffuse hypomyelination involving both large- and small-diameter fibers. Toluidine blue stain; original magnification, ×240. (Reproduced with permission from Bindu PS, Mahadevan A, Taly AB, Christopher R, Gayathri N, Shankar SK. Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India. J Neurol Neurosurg Psychiatry 2005;76(12):1698–1701.) (B) Nerve biopsy stained with cresyl violet demonstrating dense metachromatic deposits within Schwann cells obscuring the nerve fibers in the endoneurium. With acid cresyl violet, these take on a brown color (brown metachromasia), hence the term metachromatic leukodystrophy. (Reproduced with permission from http://neuropathology-web.org/.) (C) Electron micrograph showing tuff stone inclusion bodies composed of stacks of lamellar discs and plates (arrows), enclosed within a membrane in the endoneurium. Original magnification, ×10,000. (Reproduced with permission from Bindu PS, Mahadevan A, Taly AB, Christopher R, Gayathri N, Shankar SK. Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India. J Neurol Neurosurg Psychiatry. 2005;76(12):1698–1701.)





Molecular Genetics and Pathogenesis


MLD is an autosomal-recessive disorder caused by mutations in the arylsulfatase A (ARSA) or the prosaposin (PSAP) genes.18 Arylsulfatase A gene and prosaposin are both enzymes required for metabolizing galactosylsulfatide (cerebroside sulfatase), a glycolipid, present in myelin membranes. Deficiency of arylsulfatase A or the proteolytic product of prosaposin results in the accumulation of sulfatides (inclusions) in Schwann cells and oligodendrocytes resulting in dysmyelination.



Treatment


No specific medications are helpful, but bone marrow transplantation may be beneficial in some patients.19



KRABBE DISEASE (GLOBOID CELL LEUKODYSTROPHY)



Clinical Features


Krabbe disease is another autosomal-recessive myelinopathy, affecting both the CNS and the peripheral nervous system (PNS). As with MLD, Krabbe typically presents early in infancy or less frequently, in adulthood.2032 Krabbe disease usually manifests between 3 and 8 months of age. Infants who are affected often appear normal at birth but later become extremely irritable and appear hypersensitive to various stimuli which may provoke opisthotonos.24 They develop feeding difficulties, recurrent vomiting, and often generalized tonic–clonic seizures. Progressive weakness and spasticity, blindness, and deafness ensue. Muscle stretch reflexes initially may be pathologically brisk but become hypoactive as concurrent polyneuropathy worsens. Plantar responses are extensor. Death generally occurs by the age of 2 years.



Less commonly, Krabbe disease presents later in childhood or adult life with progressive dementia, spastic paraparesis or hemiparesis, cerebellar ataxia, cortical blindness, and optic atrophy.27,3133,35,36 Although peripheral neuropathy is common, it is overshadowed by the CNS abnormalities. Pes cavus and scoliosis may be seen.



Laboratory Features


Diagnosis is made by demonstrating decreased β-galactosidase activity in leukocytes or cultured fibroblasts and can be confirmed by genetic testing. Chorionic villi can be biopsied for prenatal diagnosis. Approximately 50% of the individuals affected have increased CSF protein concentrations.27,31 MRI of the brain reveals evidence of demyelination involving the corticospinal tracts and optic radiations as well as demyelination or atrophy of the posterior part of the corpus callosum.31,33,34 Motor NCS demonstrate mild to moderately reduced compound muscle action potential (CMAP) amplitudes, moderately prolonged distal latencies, moderately slow NCV, and delayed or absent F-waves.2025,27,28,3034,36 Sensory NCS reveal absent responses or SNAPs with markedly reduced amplitudes and mildly prolonged distal latencies and slow CV.



Histopathology


Moderate cortical atrophy, loss of CNS white matter, gliosis, and globoid cells (macrophages filled with galactocerebroside) are appreciated on autopsy. Nerve biopsies also demonstrate a loss of myelinated fibers and segmental demyelination or hypomyelination, and macrophages filled with galactocerebroside.21,27,3134,36,37 The abnormal inclusions within macrophages stain with periodic acid Schiff (indicating glycogen), faintly with Sudan black (indicating lipid), and with acid phosphate (suggesting that these are within lysosomes). Unlike MLD, the inclusions in Krabbe disease are not metachromatic. On EM, electron-dense granules and tubular crystalloid inclusions are evident in the cytoplasm of these histiocytes.



Molecular Genetics and Pathogenesis


Krabbe disease is autosomal recessive caused by mutations in the β-galactosidase gene (GALC) located on chromosome 14q24.3-q32.1.31,33,34 β-Galactosidase metabolizes galactocerebroside to ceramide and galactose as well as catalyzes the hydrolysis of psychosine. The abnormal accumulation of galactocerebroside and psychosine leads to the degeneration of Schwann cells and oligodendrocytes.



Treatment


There is no proven effective therapy for Krabbe disease, although bone marrow and hematopoietic stem cell transplantation may prove to be useful treatments.19,38,39



FABRY DISEASE



Clinical Features


Fabry disease (angiokeratoma corporis diffusum) is an X-linked disorder that usually affects males in childhood or adolescence.13,40,4152 Individuals who are affected typically present with burning or lancinating dysesthesia in the hands and feet. Angiokeratomas, which appear as reddish purple maculopapular lesions, are characteristically found around the umbilicus, scrotum, inguinal region, and perineum (Fig. 12-4). In addition, tiny red angiectasia may be visualized in the nailbeds, oral mucosa, and conjunctiva. The major cause of morbidity and mortality is related to accumulation of ceramide trihexoside in walls of blood vessels leading to hypertension, renal failure, coronary artery disease, strokes, and death by the fifth decade of life. Occasionally, women develop a mild painful sensory neuropathy but only rarely do they have significant atherosclerotic disease.




Figure 12-4.


Fabry disease. Anterior chest with multiple, tiny, red, and hyperkeratotic papules. (Reproduced with permission from Sodaifi M, Aghaei S, Monabati A. Cutaneous variant of angiokeratoma corporis diffusum associated with angiokeratoma circumscriptum. Dermatol Online J. 2004;10(1):20.)





Laboratory Features


A decrease in α-galactosidase activity can be demonstrated in leukocytes or cultured fibroblasts. Diagnosis can be confirmed by genetic testing. Prenatal diagnosis can be made by amniocentesis. NCS are usually normal but mildly decreased amplitudes of motor, and sensory NCS may be seen.4047 Quantitative sensory testing reveals impaired temperature perception indicative of small fiber dysfunction.44,45,47,49,50



Histopathology


Nerve biopsies are not routinely done, but they can reveal a marked reduction of small myelinated and unmyelinated nerve fibers (Fig. 12-5). Glycolipid granules may be appreciated in ganglion cells of the peripheral and sympathetic nervous systems and in perineurial cells.42,43 Reduced epidermal nerve fiber density may also be seen on skin biopsies.46,4850




Figure 12-5.


Fabry disease. Nerve biopsy. A toluidine blue-stained, semithin, plastic-embedded section reveals mild, patchy loss of large myelinated fibers, a few thinly myelinated axons, and several regenerative axon clusters (A). The perineurium (right edge) contains osmiophilic inclusions (arrows). Higher power reveals dark osmiophilic deposits in the perineurium (long arrows) and in association with blood vessels (short arrow) (B). An electron photomicrograph of the muscle biopsy specimen reveals electron-dense amorphous and lamellated inclusions in the perinuclear, subsarcolemmal region (C). (Reproduced with permission from Lacomis D, Roeske-Anderson L, Mathie L. Neuropathy and Fabry disease. Muscle Nerve. 2005;31:102–107.)





Molecular Genetics and Pathogenesis


Fabry disease is caused by mutations in the α-galactosidase gene (GLA) located on chromosome Xq21–22. Decreased α-galactosidase enzyme activity leads to the accumulation of ceramide trihexoside in nerves and blood vessels.



Treatment


Enzyme replacement therapy with agalactosidose-beta may improve the neuropathy if patients are treated early prior to irreversible nerve fiber loss.5054




PEROXISOMAL DISORDERS



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Peroxisomes are organelles within the cytoplasm that contain enzymes essential in fatty acid oxidation (distinct from mitochondrial enzymes associated with β-oxidation), bile acid and cholesterol synthesis, and amino acid metabolism. These disorders are the result of mutations in genes encoding for structural proteins or specific peroxisomal enzymes.



ADRENOLEUKODYSTROPHY/ADRENOMYELONEUROPATHY



Clinical Features


Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are allelic X-linked dominant disorders. ALD is more common and manifests in young males as progressive dementia, optic atrophy, cortical blindness, hearing loss, seizures, and spasticity.13,5562 At least 90% of patients with ALD also have adrenal insufficiency. The onset of symptoms in ALD is usually between the age of 4 and 8 years, and death usually occurs within 2 years of onset of symptoms. Less commonly, ALD develops in adolescence or young adult life and progresses at a slower rate. Affected individuals may be misdiagnosed as having multiple sclerosis. Later-onset cases may also present with psychiatric symptoms leading to misdiagnosis as schizophrenia.



Approximately 30% of cases present with the AMN phenotype and usually manifests in the third to fifth decade of life.58,61,63 Individuals affected develop progressive spastic paraplegia along with a mild to moderate peripheral neuropathy. Muscle stretch reflexes may be normal or reduced. Progressive dementia indicative of cerebral involvement can develop in some patients later in the course of the disease. Adrenal insufficiency is evident in approximately two-thirds of patients. Rare patients present with an adult-onset spinocerebellar ataxia or only with adrenal insufficiency.



Although these are X-linked disorders, women occasionally develop symptoms. Manifesting women carriers usually develop a myelopathy later in life (average age in late thirties) and again are often misdiagnosed with multiple sclerosis or familial spastic paraparesis.58



Laboratory Features


Diagnosis is made on finding that very long–chain fatty acid (VLCFA) levels (C24, C25, and C26) are increased in the serum.61,64 The ratio of hexacosanoic acid to docosanoic or erucic acid (C26:C22) and tetracosanoic acid to docosanoic acid (C24:C22) are increased in both ALD and AMN. VLCFA levels can be assessed in neonates and can be used to screen for the disease shortly after birth. Because VLCFA levels are similar in ALD and AMN, these are not helpful in predicting the clinical phenotype. As many as 85% of obligate female carriers also have elevated VLCFA levels. Some, but not all, individuals have laboratory evidence of adrenal insufficiency. Diagnosis is confirmed by genetic testing.



MRI scans reveal confluent subcortical white matter demyelination in ALD, preferentially in the posterior parietal–occipital regions (Fig. 12-6).60 MRI abnormalities of the cerebral white matter also develop later in the course in nearly half of patients with AMD but are not uniformly present in late-onset cases.




Figure 12-6.


Cerebral T2-weighted MRI of an 8-year-old boy with impaired visual acuity and seizures due to adrenoleukodystrophy. (Reproduced with permission from van Geel BM, Assies J, Wanders RJA, Barth PG. X-linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy. J Neurol Neurosurg Psychiatry. 1997;63(1):4–14.)





NCS are usually normal in ALD. However, AMN is usually associated with a sensorimotor polyneuropathy. Typically, sensory and motor NCS reveal slightly reduced amplitudes, prolonged distal latencies, and slight slow CVs, suggesting a primary axonopathy with secondary demyelination.55,56,59,62,63,65,66 Occasionally, patients fulfill electrophysiological criteria for a primary demyelination.67 Somatosensory and visual-evoked potentials demonstrate evidence of central slowing.57,59



Histopathology


We do not perform nerve biopsies routinely, but they can demonstrate a loss of myelinated and unmyelinated nerve fibers. On EM, lamellar inclusions are evident in the cytoplasm of Schwann cells (Fig. 12-7). Autopsies in ALD demonstrate demyelination and perivascular inflammation, particularly in the parietal and occipital regions.58 The spinal cord displays bilateral, usually symmetrical, long tract degeneration, particularly of the gracile tract in a dying-back pattern.67




Figure 12-7.


Adrenoleukodystrophy. Characteristic cellular inclusions (trilamellar membranes containing VLCFA cholesterol esters) are seen with the electron microscope in adrenal cortical cells, white matter histiocytes, Leydig cells, and Schwann cells. (Reproduced with permission from http://neuropathology-web.org/.)





Molecular Genetics and Pathogenesis


ALD and AMN are caused by mutations in the peroxisomal transmembrane adenosine triphosphate-binding cassette transporter gene (ABCD1), located on chromosome Xq28.58,61 The ABC transporter protein is part of peroxins family of proteins, which are involved in the transport, biogenesis, and proliferation of peroxisomes.68 There is no clear genotype–phenotype correlation associated with any specific mutation, and phenotypic heterogeneity can be found even within the family members who carry the same genetic mutation. Mutations in the gene cause impaired transport of VLCFA or VLCFA CoA synthetase into peroxisomes, thus decreasing β-oxidization of VLCFA; but how this leads to dysmyelination and axonal degeneration is not known.



Treatment


Adrenal insufficiency is managed by replacement therapy. There is however no proven effective therapy for the neurologic manifestations of ALD and AMN.58 Diets low in VLCFAs and supplemented with Lorenzo oil (erucic and oleic acids) reduce the levels of VLCFAs and increase the levels of C22 in serum, fibroblasts, and liver; however, such changes have not been consistently noted in the brain.69 Rare reports suggest clinical and MRI improvement in individual patients treated with Lorenzo oil, but several large open-label trials of Lorenzo oil failed to demonstrate significant efficacy.61,70,71 Bone marrow transplantation has also been suggested in patients with early ALD or AMN.19,61



REFSUM DISEASE (HMSN IV)



Clinical Features


Refsum disease is a peroxisomal disorder associated with impaired α-oxidation of phytanic acid. The disease can manifest in infancy to early adulthood with the classic tetrad of (1) peripheral neuropathy, (2) retinitis pigmentosa (often the earliest symptom which manifests as night blindness), (3) cerebellar ataxia, and (4) elevated CSF protein concentration.7277 Patients with Refsum disease may also develop sensorineural hearing loss, cardiac conduction abnormalities, ichthyosis, and anosmia. Some or all of these clinical findings are usually manifest in the majority of patients by the end of the second decade. Infantile Refsum disease falls within the clinical spectrum of Zellweger syndrome and neonatal ALD, albeit much milder in severity.



Although not typically a presenting manifestation, most individuals who are affected develop distal numbness and paresthesia in the legs by their twenties. The distal legs become atrophic and weak and patients develop progressive foot drop. Subsequently, the proximal leg and arm muscles may become weak. Interestingly, the neuropathy can have a fluctuating course. On examination, a length-dependent loss of vibration, proprioception, and light touch is appreciated. Hypertrophic nerves may be palpated. Muscle stretch reflexes are reduced or absent throughout.



Laboratory Features


Serum phytanic acid levels are elevated, usually greater than 200 μmol/L, as may the CSF protein concentration. Other abnormalities include an increased phytanic acid/pristanic acid ratio, elevated pipecolic acid concentration, and reduced phytanoyl-CoA hydroxylase enzyme activity. Genetic testing can be done to confirm the disorder. Sensory NCS reveal reduced amplitudes and prolonged latencies/slow CVs.76 Motor NCS demonstrate normal or moderately reduced amplitudes, mildly or moderately prolonged distal latencies, and mild to marked slowing of CV to the 10–30 m/s range.72,74,75



Histopathology


Nerve biopsies demonstrate a loss of myelinated nerve fibers, with remaining axons often thinly myelinated and associated with onion-bulb formation.



Molecular Genetics and Pathogenesis


Refsum disease is autosomal recessive and can be caused by mutations in two different genes.78 Classical Refsum disease with childhood or early adult onset is caused by mutations in the gene that encodes for phytanoyl-CoA α-hydroxylase (PHYX) located on chromosome 10p13 in 90% of affected individuals.79,80 This peroxisomal enzyme helps catalyze α-oxidation of phytanic acid. The defect leads to the accumulation of phytanic acid in various organs including the CNS and PNS, leading to neuronal degeneration. Less common, mutations in the gene that encodes for peroxin 7 receptor protein (PRX 7) located on chromosome 6q22–24 are responsible for Refsum disease.78,81,82 Mutations in the PEX7 gene that encodes for the peroxisome-targeting signal type 2 receptor are seen in less than 10% of individuals. Mutations in PEX7 also cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder.



Treatment


Refsum disease is treated by removing phytanic precursors (phytols: fish oils, dairy products, and ruminant fats) from the diet. In addition to the noticed clinical improvement, the NCS also improve with appropriate dietary restrictions as well as with plasma exchange.7275



TANGIER DISEASE



Clinical Features


Tangier disease is a rare autosomal-recessive disorder associated with a deficiency of high-density lipoprotein. The first reported patients came from Tangier island located in Chesapeake Bay—thus the name. Tangier disease may present as (1) an asymmetric mononeuropathy multiplex, (2) a slowly progressive symmetric polyneuropathy predominantly in the legs, or (3) a pseudosyringomyelia appearance in which there is dissociation between loss of pain/temperature and position/vibration in the arms.8392 Deposition of cholesterol esters within the tonsils leads to their swollen, yellowish-orange appearance. In addition, splenomegaly and lymphadenopathy may be apparent.



Laboratory Features


Serum high-density lipoprotein cholesterol levels are markedly reduced while triacylglycerol levels are increased. Genetic testing is available to confirm the diagnosis. Motor and sensory NCS can be normal or associated with moderately reduced amplitudes, prolonged distal latencies, partial conduction block, and slow CVs.8488,90,91 The asymmetric nature of the polyneuropathy and demyelinating features including conduction block may mimic Lewis–Sumner syndrome (e.g., multifocal acquired demyelinating sensory and motor neuropathy or MADSAMN—see Chapter 14).90,91



Histopathology


Nerve biopsies are not required for the diagnosis, but studies have reported they reveal axonal degeneration with demyelination, remyelination, and redundant myelin folds (i.e., tomacula).83,9294 EM demonstrates abnormal accumulation of lipid in Schwann cells, particularly those encompassing unmyelinated and small myelinated nerve (Fig. 12-8).83,92 There appears to be preferential involvement of noncompacted myelin region of the paranode for lipid storage in the myelinated Schwann cells.




Figure 12-8.


Tangier disease. Electron micrographs. (A) Transverse section showing multiple electron-lucent vacuoles in the cytoplasm of unmyelinated Schwann cells. (B) Longitudinal section showing linearly arranged vacuoles in Schwann cell cytoplasm of an unmyelinated axon (ua). (C) Multiple vacuoles in a fibroblast. (D) Small vacuoles in the disrupted paranodal myelin terminal loops. (E) Large vacuoles in the paranodal abaxonal Schwann cell cytoplasm. Bar = 1 μm. (Reproduced with permission from Cai Z, Blumbergs PC, Cash K, et al. Paranodal pathology in Tangier disease with remitting-relapsing multifocal neuropathy. J Clin Neurosci. 2006;13(4):492–497.)





Molecular Genetics and Pathogenesis


Tangier disease is caused by mutations in the ATP-binding cassette-1 gene (ABCA1) located in chromosome 9q22–31.95,96 The pathogenic basis of the peripheral neuropathy is unknown but may be similar to ALD/AMN, which are also caused by mutations involving the ABC transporter superfamily.



Treatment


There is no specific treatment.



CEREBROTENDINOUS XANTHOMATOSIS (CHOLESTANOLOSIS)



Clinical Features


Cerebrotendinous xanthomatosis is a rare autosomal-recessive disorder that usually presents after the second decade with progressive dementia, spasticity, ataxia, and a mild sensory neuropathy.97104 The name of the disorder arises because of the common occurrence of xanthomas on tendons and the skin. Cataracts are another frequent complication. Most individuals who are affected die in the fourth decade of life because of complications from premature atherosclerosis.



Laboratory Features


Serum level of cholestanol is increased. Genetic testing can be performed to confirm the diagnosis. NCS are variable, depending on the presence and the degree of severity of peripheral neuropathy.97,99,100,103 Motor and sensory may be normal or reveal absent amplitudes, with slightly prolonged distal latencies, and mildly slow CVs suggestive of an axonal sensorimotor polyneuropathy.



Histopathology


Nerve biopsies reveal a loss of myelinated nerve fibers with variable degrees of demyelination and onion-bulb formation. Lipid inclusions are evident in Schwann cells.



Molecular Genetics and Pathogenesis


This disorder is caused by mutations in the sterol 27 hydroxylase gene located on chromosome 2, which results in impaired metabolism of cholestanol, the 5α-dihydro derivative of cholesterol.105 Cholestanol accumulates in body tissues, including peripheral nerves, thereby resulting in the associated clinical features.



Treatment


Early treatment with chenodeoxycholic acid may lead to a decrease in serum cholestanol and diminished excretion of bile alcohols in urine accompanied by clinical improvement.98 Motor and sensory NCS improved in one patient following plasma exchange and treatment with chenodeoxycholic acid.99




HEREDITARY ATAXIAS



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The hereditary ataxias are a group of progressive neurodegenerative disorders characterized by varying degrees of degeneration of the cerebral cortex, basal ganglia, cerebellum, brainstem, corticospinal tracts, spinocerebellar tracts, motor neurons, and peripheral nerves (Table 12-1). The associated peripheral neuropathy with some of these disorders is usually overshadowed by the CNS abnormalities. However, the neuropathy can be quite prominent in Friedreich ataxia (FA) and an inherited form of vitamin E deficiency.



FRIEDREICH ATAXIA



Clinical Features


FA usually presents between 2 and 16 years of age with gait ataxia (63%), generalized clumsiness (25%), difficulty ambulating (4%), scoliosis (5%), tremor (1%), and cardiomyopathy (2%).106113 However, several genetically confirmed late-onset cases have been described.108,114,115 FA is the most common form of autosomal-recessive ataxia. Dysarthria, optic atrophy, pigmentary retinopathy, nystagmus, reduced hearing, ataxia, pyramidal and lower motor neuron weakness, distal limb atrophy, scoliosis, and pes cavus are evident on examination. In addition, reduced vibratory sensation and proprioception associated with diminished muscle stretch reflexes are seen, often associated with extensor plantar responses.108,114,115 Rarely, affected individuals have retained reflexes.116 Some patients develop dementia. FA is a progressive disorder and most patients are wheelchair dependent with 15 years of onset of symptoms. There is increased mortality with the mean age of death in the mid to late thirties.

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Dec 31, 2018 | Posted by in PSYCHIATRY | Comments Off on Other Hereditary Neuropathies

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