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NORD is very grateful to Deborah L. Renaud, MD, Departments of Neurology and Pediatrics, Mayo Clinic; Ann B. Moser, MA, The Hugo W. Moser Research Institute, Kennedy Krieger Institute; and Hugo Moser, MD, deceased, former Director of the Neurogenetics Research Center at Kennedy Krieger Institute, for assistance in the preparation of this report.
Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.
Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. Some inherited leukoencephalopathies have stable white matter abnormalities.
Magnetic resonance imaging (MRI) has markedly increased the awareness of hereditary white matter diseases associated with the formation of myelin and hypomyelination, in addition to the previously described classic leukodystrophies. New disease entities based on MRI and clinical patterns have been defined through the committed collaboration of neurologists in medical centers around the world. While the following list includes many disorders that have recently been described, it is not complete as there are new leukodystrophies identified each year. With the advances in whole genome sequencing, there will be many more new genetic disorders found including those that affect the white matter of the brain.
For more information on the following disorders, search the Rare Disease Database.
Aicardi-Goutieres syndrome is an autosomal recessive condition, presenting with an early encephalopathy followed by stabilization of neurologic symptoms. At least four different genes have been described. Neuroimaging reveals leukoencephalopathy with calcifications and cerebral atrophy. Cerebrospinal fluid analysis reveals chronic lymphocytosis (elevated white blood cell count), elevated INF-a, and neopterin.
Alexander disease is an extremely rare, progressive, leukodystrophy that usually becomes apparent during infancy or early childhood but juvenile and adult onset forms have also been reported. Alexander disease is characterized by degenerative changes of the white matter of the brain caused by a lack of normal amounts of myelin. The disorder is also associated with the formation of abnormal, fibrous deposits known as "Rosenthal fibers" in the astrocytic processes around small blood vessels and astrocytic cell bodies in certain regions of the brain and spinal cord. The disease is caused by a dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) (Chromosome 17q21). Treatment for Alexander's disease is currently symptomatic consisting of anticonvulsants for seizures, orthopedic and pharmacologic management of spasticity, and nutritional support. Strategies for future treatment include decreasing the expression of GFAP.
CADASIL is a rare genetic disorder with dominant inheritance caused by a mutation in the NOTCH3 receptor gene. This condition presents with migraine headaches and multiple strokes in adults, even young adults, often without cardiovascular risk factors. CADASIL often progresses to cause cognitive impairment and dementia. The symptoms of CADASIL result from damage of various small blood vessels, especially those within the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:
(C)erebral - relating to the brain
(A)utosomal (D)ominant - a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy - disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical - relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts - tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy - destruction of the myelin, that covers and protects nerve fibers in the central nervous system
Canavan disease is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Physical symptoms that appear in early infancy may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally large head (macrocephaly), and/ or irritability. Physical symptoms appear in early infancy and usually progress rapidly. Canavan disease is caused by an abnormality in the ASPA gene (Chromosome 17p13-ter0) that leads to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited as an autosomal recessive genetic disorder. There are two common mutations among the Ashkenazi Jewish individuals that account for over 97% of the alleles in Jewish patients with Canavan disease.
CARASIL is rare autosomal recessive disorder that is caused by mutations in cerebral small-vessel disease protein HTRA1 that controls the amount of TGF-B1 via cleavage of proTGF-B1b. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or leukoaraiosis (changes in deep white matter in the brain, which are observed on MRI). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs, and pseudo bulbar palsy beginning between 20 and 30 years of age. Pseudo bulbar palsy is a group of neurologic symptoms including difficulties with chewing, swallowing and speech. Eventually, cognitive impairment and dementia may result. About half of cases have a stroke-like episode. The age of onset is 20 to 50 years old. CARASIL is an acronym that stands for:
(C)erebral - relating to the brain or the cerebellum, which is the part of the brain that controls balance and muscular coordination
(A)utosomal (R)ecessive - a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy - disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical - relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts - tissue loss in the cerebellum caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy - destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous system
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive genetic disorder due to mutations in the sterol 27-hydroxylase gene (CYP27A1), resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodexoycholic acid. Lipid rich deposits containing cholestanol and cholesterol accumulate in the nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals experience cataracts during childhood, and benign, fatty tumors (xanthomas) of the tendons during adolescence. The disorder leads to progressive neurologic problems in adulthood such as paralysis, ataxia and dementia. Coronary heart disease is common. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absent or inactive form of the sterol 27-hydroxylase. Dietary therapy with the bile acid, chenodeoxycholic acid, does correct many of the symptoms of CTX; however, early diagnosis of the disorder with early therapy leads to a better clinical outcome. The activity of cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis, is normalized by this diet therapy and there is a reduction in the development of xanthomas.
Childhood ataxia with cerebral hypomyelination
Childhood ataxia with cerebral hypomyelination (CACH), also known as vanishing white matter disease (VWMD), is an autosomal recessive leukodystrophy that is characterized by progressive deterioration in motor function and speech during the first five years of life. Clinical symptoms typically begin in the first few years of life, following a normal to mildly delayed early development. Common presenting symptoms include ataxia and seizures. The course is chronic and progressive with episodic decline following fever, head trauma, or periods of fright. Patients usually survive only a few years past the clinical onset, though the course is variable even among patients with mutations in the same eIF2B subunit. In the rare reports of adult-onset VWMD, the typical presentation consists of cognitive deterioration, pseudo bulbar palsy and progressive spastic paraparesis. An important association between VWMD and ovarian failure has been described, termed ‘ovarioleukodystrophy’. VWMD may be one of the more common inherited leukoencephalopathies, though its exact incidence is not yet known.
VWMD is caused by mutations in one of the 5 subunits of eukaryotic initiation factor 2B (eIF2B). eIF2B is a highly conserved, ubiquitously expressed protein that plays an essential role in the initiation of protein synthesis by catalyzing the GDP-GTP exchange on eIF2 to enable binding of methionyl-transfer-RNA to the ribosome. Despite the essential role of eIF2B in all cells, its defect curiously causes selective damage of white matter and in some cases damage to the ovaries alone. The ability of glia to regulate eIF2 activity may represent a critical protective mechanism in response to stress conditions.
Fabry disease is a progressive X-linked lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids, mainly globotriaosylceramide GL-3 in lysosomes. This accumulation triggers tissue ischemia and fibrosis. The classic form of the disease presenting in males with no detectable enzyme activity, is characterized by angiokeratomas, acroparesthesia, hyperhidrosis, corneal opacity in childhood or adolescence and progressive vascular disease of the heart, kidneys, and central nervous system. MRI findings include white matter abnormalities and vertebrobasilar stroke. In contrast, patients with mild forms of Fabry disease and residual alpha-galactosidase activity may remain asymptomatic until late adulthood. The incidence of Fabry disease is estimated to be 1/100,000; however, with the advent of newborn screening the true incidence will be determined. Recently enzyme replacement therapy and pharmacological chaperone therapy have been introduced to lower the GL-3 accumulation in the lysosome.
Fucosidosis is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood. Hypomyelination is present on the MRI scans.
The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha-L-fucosidase enzyme leads to the abnormal accumulation of fucose-containing compounds in the tissues of individuals with fucosidosis.
Glutaric aciduria type 1
Glutaric aciduria type 1 (GA1) is an autosomal recessive disorder due to a deficiency of glutaryl-CoA dehydrogenase (GCDH). Deficiency of this mitochondrial enzyme results in the accumulation of glutaric acid and 3-hydroxyglutaric acid in the blood, urine, and CSF. Greater than 100 disease-causing mutations have been identified in the GCDH gene located on chromosome 19p13.2. Common mutations have been identified in two isolated populations, the Old Order Amish in Pennsylvania and the Island Lake Indians of Manitoba. Several theories regarding the pathogenic mechanisms have been postulated, but it is unclear why some patients develop striatal necrosis (basal ganglia damage) and others do not. Newborn screening with measurement of glutarylcarnitine in the newborn blood spot by tandem mass spectrometry identifies newborns with GA1 so that implementation of prospective treatment of illness can help to prevent acute neurologic deterioration. Children who do not experience an acute encephalopathic crisis may present with a slowly progressive neurologic disorder with seizures, physical disability, and fasting hypoglycemia. Characteristic MRI findings include widening of the Sylvian fissure, enlarged ventricles and increased cerebrospinal fluid anterior to the temporal lobes.
GM1 gangliosidosis is an autosomal recessive disorder due to deficiency of the lysosomal enzyme ß-galactosidase associated with mutations in the GLB1 gene. More than 100 mutations have been described. ß-galactosidase hydrolyses the ß-galactosyl residue from GM1 ganglioside, glycoproteins, and glycosaminoglycans. Deficiency of ß-galactosidase results in lysosomal storage of these substances, particularly in the central nervous system (CNS). Three types of GM1 gangliosidosis have been described. Type 1 or infantile GM1 gangliosidosis has its onset before 6 months of age with rapidly progressive hypotonia (low body tone) and CNS deterioration resulting in death by 1 to 2 years of age. Type II or late-infantile/ juvenile GM1 gangliosidosis presents with delay in cognitive and motor development between 7 months and 3 years of age with slow progression. Adult-onset GM1 gangliosidosis presents between 3 to 30 years of age with a progressive extrapyramidal disorder. MRI findings include delayed myelination, diffuse white matter abnormalities and abnormal signal in the basal ganglia.
L-2-hydroxyglutaric aciduria is a rare autosomal recessive disorder. Mutations in both copies of the L2HDGH gene result in deficiency of L-2-hydroxyglutarate dehydrogenase activity. L-2 hydroxyglutarate dehydrogenase is an FAD-linked mitochondrial enzyme that converts L-2 hydroxyglutarate to a-ketoglutarate. Biochemically, L-2-hydroxyglutaric aciduria presents with significantly elevated levels of L-2-hydroxyglutaric acid in the urine and CSF. Plasma amino acids reveal elevated lysine. Clinically, L-2 hydroxyglutaric aciduria presents with variable degrees of psychomotor and speech delay followed by a slowly progressive neurodegenerative disorder with cognitive decline. The MRI demonstrate a complex but characteristic pattern. An increased risk of brain tumors has been described.
Krabbe disease also known as globoid cell leukodystrophy, is an autosomal recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceramide and psychosine (galactosyl-sphingosine). Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction with irritability, developmental regression, abnormal body tone, seizures and peripheral neuropathy. The MRI may appear normal early in the disease course but eventually demonstrates diffuse white matter abnormalities. More than 75 mutations have been described in the GALC gene. There is limited correlation between genotype and phenotype, with the exception of homozygosity for the common 30kb deletion being predictive of early-infantile Krabbe disease and having at least one G809A allele being compatible with juvenile or adult onset. Otherwise, the genotype–phenotype correlation is poor, making prediction of the early-infantile phenotype at birth difficult. The incidence of Krabbe disease has been estimated at 1 in 100,000, with 85 to 90% of patients having the early-infantile form, although recent newborn screening results suggest that a higher proportion of patients may have later onset forms. Early hematopoietic stem cell transplantation attenuates the clinical course of infantile Krabbe disease and prolongs survival but is not curative.
Megalencephalic leukoencephalopathy with subcortical cysts
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive condition which initially presents with macrocephaly (enlarged head size). Mild motor delay is followed by gradual motor deterioration with ataxia and spasticity. Cognitive abilities are relatively spared but seizures may occur in this classical form. Recessive MLC1 mutations are observed in 80% of patients with MLC. Other patients with the classical, deteriorating phenotype have two mutations in the HEPACAM gene. An improving phenotype has been described in patients with only one mutation in HEPACAM. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and intellectual disability with or without autism. Diffuse white matter abnormalities on MRI are accompanied by anterior temporal cysts.
Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulphatase A (ASA). This leads to the accumulation of a fatty substance known as sulfatide, sphingolipid, in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). Myelin is lost from areas of the central nervous system and peripheral nerves due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include seizures, personality changes, spasticity, progressive dementia, painful paresthesias, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Infantile, juvenile, and adult onset forms of metachromatic leukodystrophy have been distinguished. There is evidence for genotype-phenotype correlation. Patients with 2 mutations that do not allow expression of the ASA enzyme suffer from the late infantile form whereas the juvenile patients have more residual enzyme activity. ASA-deficient mice have been produced which have led to a better understanding of the disease process and to various therapeutic trials involving enzyme replacement therapy, haematopoietic stem-cell transplant and gene therapy.
Multiple sulfatase deficiency
Multiple sulfatase deficiency (MSD) is a very rare leukodystrophy in which all of the known sulfatase enzymes (thought to be seven in number) are deficient or inoperative due to mutations in the SUMF1 gene. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children.
Similar to metachromatic leukodystrophy, multiple sulfatase deficiency patients exhibit neurodegenerative disease in early childhood due to central nervous system (CNS) and peripheral demyelination with loss of sensory and motor functions. They also develop intellectual disability, hepatosplenomegaly, coarse facies, and corneal clouding as seen in patients with mucopolysaccharidoses. Ichthyosis and skeletal changes reflect enzyme deficiencies of steroid sulfatase (X-linked ichthyosis) and arylsulfatase E (chondrodysplasia punctata), respectively. The unique combination of neurodegeneration, coarse facial features, hepatosplenomegaly, and ichthyosis is not seen in other neuro-ichthyotic disorders. However, the sequential appearance of these clinical signs often delays the diagnosis of MSD.
Pelizaeus-Merzbacher disease, also known as X-linked spastic paraplegia, is a rare inherited disorder affecting the central nervous system that is associated with a lack of myelin sheath. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities, and the progressive deterioration of intellectual function. The symptoms of Pelizaeus-Merzbacher disease (PMD) are usually slowly progressive. Several forms of the disorder have been identified, including classical X-linked PMD; acute infantile (or connatal) PMD; and adult-onset (or late-onset) PMD. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). The most common form of PMD is caused by a duplication of the PLP1 gene. Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. Supportive therapy for patients with PMD/SPG2 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.
Refsum disease, also called hereditary sensory motor neuropathy type IV, is an autosomal recessive leukodystrophy in which the myelin sheath fails to grow. The disorder is caused by the accumulation of a methyl branched chain fatty acid (phytanic acid) in blood plasma and tissues due to mutations in the PHYH gene that encodes the peroxisomal enzyme phytanoyl-CoA hydroxylase that is responsible for the a-oxidation of phytanic acid. 90% of patients with Refsum disease have a mutation in the PHYH gene; whereas the remaining 10% have a mutation in the peroxisomal gene, Pex7, which is necessary for import of phytanoyl-CoA hydroxylase into peroxisomes. Refsum disease is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). Treatment with a diet low in phytanic acid and avoidance of foods such as cold water fish, dairy and ruminant meats that contain phytanic acid can be beneficial. Plasmapheresis and the intestinal lipase inhibitor, Orlistat have shown some efficacy in lowering phytanic acid levels. However these therapies, while successful at diminishing the neurological symptoms do not prevent the slow progression of retinitis pigmentosa.
Salla disease is a rare autosomal recessive disorder due to deficiency of the sialic acid transporter, SLC17A5. Free sialic acid (N-acetylneuraminic acid) accumulates in lysosomes in various tissues. The severe form, infantile free sialic acid storage disorder, results in early death. Salla's disease, which is more common in patients of Finnish descent, has wide clinical variability. Most children present between 3 and 9 months of age with hypotonia, ataxia, delayed motor milestones, and transient nystagmus. Cognitive delay and slow motor decline occurs after the second to third decade. Peripheral neuropathy may be present and contribute to motor disability. MRI findings are consistent with hypomyelination with minimal or extremely slow myelination. Myelin is present in the internal capsule and is usually normal in the cerebellum. The corpus callosum is usually thin. Treatment for Salla's disease is supportive.
Sjögren-Larsson syndrome (SLS) is caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase is located on chromosome 17p11.2. More than 70 different mutations in the ALDH3A2 gene have been identified in SLS patients originating from about 120 different families. Fatty aldehyde dehydrogenase is necessary for the oxidation of long-chain aldehydes and alcohols to fatty acids. Deficiency of this enzyme leads to accumulation of these lipids leading to increased inflammatory lipids, the leukotrienes, in skin and brain, which are thought to be directly responsible for the symptoms of ichthyosis and delay in myelination. About 70% of SLS patients are born preterm most likely due to the fetal excretion of abnormal lipids and leukotrienes causing inflammation and early labor. During early childhood (1–2 years of age) intellectual and motor disabilities gradually become clear, however, the typical MRI and H-MRS abnormalities, as well as crystalline maculopathy, may be absent, and normal radiologic and ocular findings do not exclude SLS at this stage. Later on in childhood (from 3 years of age), the full-blown phenotype of SLS with the classical triad of ichthyosis, spasticity, and intellectual disability is present with the typical findings of ophthalmological and MRI/H-MRS studies. Therapies consist of preventing skin lesions through application of special creams and urea-containing emollients and physical therapy and bracing to diminish contractures. Therapies to reduce the levels of leukotrienes, to prevent the skin lesions and improve neurological functioning are being studied.
X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy and affects the myelin or white matter of the brain and the spinal cord as well as the adrenal cortex. The gene for ALD, the ABCD1 gene, is located at Xq28 and encodes a peroxisomal protein belonging to the ATPase Binding Cassette proteins. There have been more than 1000 mutations reported in the ABCD1 gene (www.x-ald.nl). ALD is a progressive disease characterized by an accumulation of very long chain fatty acids, mainly of 26 carbons in chain length. There are several phenotypes of ALD, each distinguished by the age of onset and by the features that are present. All phenotypes can occur in the same kindred with 31-35% of affected males having the demyelinating childhood cerebral form (CCER) with typical onset between 4 and 8 yrs. Boys develop normally until the onset of dementia and progressive neurologic deficits which lead to a vegetative state and death often within 3 yrs. Forty to 46% of males with ALD present in early adulthood with slowly progressive paraparesis (weakness and spasticity), sensory, and sphincter disturbances involving spinal cord long tracts. This form is called adrenomyeloneuropathy (AMN). At least 30% of men with AMN develop cerebral involvement that is similar to CCER. Fifty per cent of heterozygous females (carriers) develop overt neurologic disturbances resembling AMN, with a mean age of onset of 37 yrs. The minimum frequency of hemizygotes (i.e., affected males) identified in the United States is estimated at 1:21,000 and that of hemizygotes plus heterozygotes (i.e., carrier females) 1:16,800.
Untreated adrenal insufficiency can be fatal and untreated CCER is fatal. Earlier onset of CCER correlates with more severe, rapidly progressive clinical manifestations. Boys with parieto-occipital lobe disease demonstrate visual and/or auditory processing abnormalities, impaired communication skills and gait disturbances prior to death. Boys with frontal lobe involvement have signs/symptoms similar to ADHD and are often misdiagnosed prior to death. The extent of demyelination can be quantitated using the MRI severity score of Loes.
ALD in boys can be diagnosed by analysis of the very long chain fatty acids in plasma and if positive, mutation analysis of the ABCD1 gene is recommended. For females at risk of ALD, the most accurate test is targeted analysis of the family mutation in the ABCD1 gene as the plasma very long chain fatty acid test for females has a 20% false negative rate due to lyonization of the X-chromosome. It is important to screen all at-risk relatives for ALD as the males with ALD are at risk for Addison disease which is treatable with life-saving hormone therapy. Dietary therapy with Lorenzo’s oil if started early before MRI abnormalities occur and if plasma levels of very long chain fatty acids are normalized, has shown to statistically lower the development of CCER. Over one third of ALD boys will develop CCER thus ALD boys who are diagnosed before neurological symptoms occur should be followed by a pediatric neurologist and have MRI every 6 months. At first signs of progressive white matter abnormalities on MRI, bone marrow transplantation, or hematopoetic cell transplantation (HCT), is recommended as the only effective long-term treatment for CCER; however, to achieve optimal survival and clinical outcomes, HCT must occur prior to manifestations of symptoms. Gene therapy experimental treatment has been shown to be safe and efficacious.
With the development of a newborn screening test for ALD all boys with ALD will be diagnosed at an age before Addison disease and brain dysfunction occur. Thus life-saving therapies can be implemented early and other at risk relatives identified.
Zellweger syndrome spectrum disorders
Zellweger syndrome spectrum disorders, also known as peroxisomal biogenesis disorders (PBDs), are characterized by a deficiency or absence of peroxisomes in the cells of the liver, kidneys, and brain. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that function as part of the body's waste disposal system. In the absence of the enzymes normally found in peroxisomes, waste products, especially very long chain fatty acids (VLCFA), accumulate in the cells of the affected organ. The accumulation of these waste products has profound effects on the development of the fetus. PBDs are inherited as autosomal recessive disorders and have two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. There is genetic heterogeneity among PBDs and this is present in all defective PEX genes. The PBDs with the mildest phenotype are known by the clinical names, neonatal adrenoleukodystrophy and infantile Refsum’s disease. A range of symptoms are seen including developmental delay, sensorineural hearing loss, visual abnormalities, adrenal insufficiency and liver dysfunction. MRI scans may show developmental abnormalities of the brain and progressive white matter changes may develop. Diagnosis of PBDs is made by finding an increase in the plasma very long chain fatty acids (VLCFA) and the branched chain fatty acids, phytanic and pristanic. Additional biochemical laboratory tests are the measurement of red blood cell plasmalogens, the plasma and urine pipecolic acid, the peroxisomal bile acid intermediates, and the peroxisomal enzymes in cultured skin fibroblasts, which involve 1) determination of the VLCFA levels; 2) evaluation of the capacity of the cells to perform peroxisomal C26:0 and pristanic acid ß-oxidation; 3) evaluation of the capacity of the cells to perform peroxisomal phytanic acid a-oxidation; 4) analysis of the activity of ihydroxyacetonephosphate acyltransferase; and 5) catalase immunofluorescence (IF) microscopy to assess the absence or phenotype of peroxisomes in the cells. Genetic testing for mutations in one of the 14 PEX genes is done in organized screening looking for mutations in the most common PEX genes. If no mutation is found, complementation analysis of cultured skin fibroblasts is performed to find the defective PEX gene followed by complete sequencing of the defective PEX gene. Therapies are available for the milder phenotypes and include bile acid therapy for liver dysfunction, dietary therapy for increased phytanic acid, and docosahexaenoic acid (DHA) therapy.
Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development or destruction of the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or autosomal dominant. Some dominantly inherited conditions result from a de novo mutation. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The leukodystrophies can affect either adults or children, but are more common in children. Some types of leukodystrophy affect males and females equally but other types predominantly affect males.
Symptoms of the following disorder can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects adults, and its cause is unknown.
Treatment of most leukodystrophies is symptomatic and supportive. Medications and physical therapy may be helpful for spasticity and motor difficulties. Anti-epileptic medications should be provided for seizures and burning paresthesia from peripheral neuropathy may respond to medications for neuropathic pain. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.
IInformation on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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Report last updated: 2013/09/10 00:00:00 GMT+0