Schindler disease

Disease Overview

Schindler disease is a rare inherited metabolic disorder characterized by the deficient activity of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA or alpha-galactosidase B). The enzyme defect leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides), which have terminal or preterminal N-acetylgalactosaminyl residues in many tissues of the body and in urine. Two major forms of Schindler disease exist – a severe form with onset in infancy (type I) and a milder form with onset in adulthood (type II). Some researchers have proposed a type III form of Schindler disease that is less severe than type I, but more severe than type II. The specific symptoms and severity of Schindler disease can vary from one person to another. Schindler disease is caused by mutations of the NAGA gene and is inherited as an autosomal recessive trait.

Schindler disease belongs to a group of diseases known as lysosomal storage disorders. Within cells, lysosomes are small compartments or organelles which are bound by membranes. They function as the primary digestive units of cells. Enzymes within lysosomes break down or digest particular nutrients and cellular debris. Low levels or inactivity of these enzymes leads to the abnormal accumulation of the substances that they normally breakdown, resulting in the enlargement and increased numbers of lysosomes within cells of the body, as well as leakage of their stored contents. These disturbances may interfere with normal cellular function and cause the disease manifestations.

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Synonyms

• Alpha-N-Acetylgalactosaminidase deficiency
• NAGA deficiency
• neuroaxonal dystrophy, Schindler type

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Subdivisions

• Kanzaki disease
• Schindler disease Type I
• Schindler disease Type II
• Schindler disease Type III

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Signs & Symptoms

Some researchers have broken Schindler disease into three distinct types. Type I is a severe form that occurs during infancy and is associated with neurological symptoms. Type II is a milder form of the disorder with onset usually in adulthood and mild, if any associated neurological symptoms. Type III is an intermediate form whose onset and severity fall in between the other two. Consequently, the severity and specific symptoms of Schindler disease can vary greatly from patients in one family to those in another.

It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

SCHINDLER DISEASE TYPE I

Schindler disease type I, the classic form of the disease, begins in infancy. Affected children develop normally until approximately 9 months to 1 year of age. They may then begin to exhibit a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). After a period of such developmental delays, affected children may begin to lose previously acquired physical and mental abilities (developmental retrogression); such regression may begin at approximately 2 years of age. Affected children may then start to exhibit a variety of neurological symptoms, such as muscular weakness and diminished muscle tone (hypotonia); involuntary muscle spasms that result in slow, stiff movements (spasticity), misalignment of the eyes (strabismus); involuntary, rapid eye movements (nystagmus); and/or visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy). They may also experience brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic movements and grand-mal seizures).

SCHINDLER DISEASE TYPE II

In the adult-onset form of Schindler disease (also known as Schindler disease type II or Kanzaki disease), symptoms may not appear until the second or third decade of life. A distinctive symptom of Schindler disease type II is involvement of small blood vessels (telangiectasia) in the skin that cause reddish small skin lesions, and an increase of its horny layer (stratum corneum; hyperkeratosis) referred to as angiokeratomas. The dilation of small lymph vessels may lead to swelling (lymphedema) particularly of the lower extremities.

Angiokeratomas may first be restricted to a single area (localized), such as the lower torso, and then appear later in additional locations (e.g., from the lower torso to the chest area). These reddish lesions may be flat or raised and vary in color, and may occur in clusters. Affected individuals may also have these lesions in other areas of the body such as the mucous membranes including the mouth and eyes.

Individuals with Schindler disease type II have also mild intellectual impairment, but do not show the serious neurological complications associated with Schindler disease type I. Individuals with Schindler disease type II may also develop distinctive facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Additional symptoms have been reported in the medical literature including vertigo, hearing loss, ringing in the ears (tinnitus), and muscle weakness. Patients may also experience pain crises. Many of the latter manifestations are thought to be due to lysosomal storage.

SCHINDLER DISEASE TYPE III

Schindler disease type III, is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms.

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Causes

Schindler disease is caused by mutations in the NAGA gene. These mutations are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of mutations for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait 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, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.

Investigators have determined that the NAGA (alpha-N-acetylgalactosaminidase) gene is located on the long arm (q) of chromosome 22 (22q13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 22q13.2” refers to band 13 sub-band 2 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Investigators have determined that the NAGA gene contains instructions for generating (encoding) an enzyme known as alpha-N-acetylgalactosaminidase (alpha-NAGA). All three forms of Schindler disease are characterized by very low levels or deficient activity of this enzyme. Low levels or absent activity of the enzyme leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides) in certain tissues of the body and in urine.

Although mutations in the NAGA gene are clearly linked to the accumulation of the complex compounds containing alpha-N-acetylgalactosaminyl residues in the body, some researchers have questioned whether mutations in the NAGA gene cause the neurological symptoms associated with Schindler disease. Although all individuals with Schindler disease have mutations in the NAGA gene, not all develop neurological symptoms. The severe neurological symptoms of type I Schindler disease are associated with characteristic swellings at the end of nerve fibers (axons). These swellings may be referred to as dystrophic axonal swellings or “spheroids”. The spheroids are characteristic of a neuroaxonal dystrophy – a severe alteration of nerve cells. These swellings appear to disrupt proper nerve function by blocking the transmission of impulses between nerve cells. Some researchers suspect that other factors in addition to or instead of mutations of the NAGA gene may cause the development of the neurological symptoms of Schindler disease. For example, some researchers have speculated that individuals with Schindler disease who have neurological symptoms may have additional mutations in an unrelated gene. However, no conclusive evidence exists to confirm this theory. More research is necessary to determine the exact complex mechanisms that ultimately cause the neuroaxonal dystrophy of Schindler disease.

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Affected populations

Schindler disease affects males and females in equal numbers. The exact incidence of Schindler disease in the general population is unknown. Because cases of Schindler disease may go unrecognized or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. As a group, lysosomal storage diseases are infrequent, although certain disorders may occur in specific ethnic or demographic groups at higher frequencies, about one in every 1,000-2,000 live births for Gaucher and Fabry diseases, or very infrequently (1 in 100,000 to 200,000 live births) for most of these disorders, which may be the case for alpha-N-acetylgalactosaminidase deficiency. Schindler disease was first reported in the medical literature in the late 1980s.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Schindler disease. Comparisons may be useful for a differential diagnosis.

Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare, inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axon terminals) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with INAD appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Patients experience a rapid and severe course of neurodegeneration with loss of all previously acquired mental and motor skills. The symptoms and physical characteristics associated with INAD are the result of swelling and degeneration of nerve endings (dystrophic axonal swellings or “spheroids”, virtually identical to those in Schindler disease type I) within and without areas of the brain and spinal cord (central nervous system). INAD is inherited as an autosomal recessive genetic trait. About 60% of patients with INAD have been associated with mutations in the PLA2G6 gene encoding a cytosolic, calcium-independent phospholipase A2 (group IV). Intriguingly, mutations in that gene have also been detected in patients with other neurodegenerative disorders such as early-onset Parkinsonism and Dystonia, and there remain INAD patients without PLA2G6 mutations. Besides the relatively uniform manifestations of classic INAD, some researchers have suggested an atypical form of INAD with later-onset, milder, and divergent symptoms that overlap with those of neurodegeneration with brain iron accumulation (NBIA; Hallervorden-Spatz syndrome), see below. (For more information on this disorder, choose “infantile neuroaxonal dystrophy” as your search term in the Rare Disease Database.)

NBIA is a clinically and genetically heterogeneous group of rare, inherited, neurological movement disorders of childhood, characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Two genes for the major forms of NBIA have been identified, but there remain patients without mutations in either gene. The disease that is associated with mutations in the pantothenate kinase 2 gene, PANK2, is termed pantothenate kinase-associated neurodegeneration (PKAN). Approximately 50% of individuals with a clinical diagnosis of NBIA have gene mutations in PANK2. Its product normally helps to metabolize vitamin B5 (pantothenic acid) to synthesize coenzyme A. Classical PKAN begins with clumsiness and gait (walking) problems around age 3 years. Common features include dystonia, (an abnormality in muscle tone), muscular rigidity, and sudden involuntary muscle spasms (spasticity). These features can result in difficulty controlling movement and in speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. In general, symptoms are progressive and become worse over time. There is also an atypical form of PKAN that is recognized with later-onset and more slowly progressive neuropsychiatric features in addition to a movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. There are different mutations within PANK2 that could lead to a more or less severe presentation. Other factors that influence disease severity and the rate of progression are still unknown. Many of non-PKAN NBIA patients reveal mutations in the PLA2G6 gene. Clinically, these patients may have a static encephalopathy during childhood and then present in adulthood with a degenerative course, or they may have a hyperkinetic movement disorder from early childhood, or they constitute a subset of INAD patients with high globus pallidus iron. Finally, there are non-PKAN patients without mutations in PLA2G6. Other genes that have been associated with non-PKAN NBIA include FA2H, ATP13A2, C2orf37, CP, and FTL. (For more information on this disorder, choose “neurodegeneration with brain iron accumulation” as your search term in the Rare Disease Database.)

Fabry disease is a rare genetic disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A. The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Absence or less than 1 percent of the alpha-galactosidase A enzyme results in the “classic” subtype of Fabry disease due to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various cells and organs of the body, particularly in the cells of blood vessels. Symptoms of “classic” Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), excruciating pain in the fingers and toes, and abdominal pain. Later in the course of the disease, kidney failure, heart disease, and/or strokes cause serious complications. Fabry disease, which is inherited as an X-linked trait, affects males and females. Males are more uniformly affected whereas females may be asymptomatic or as severely affected as males due to “skewing of X-inactivation.” Patients with alpha-galactosidase A levels greater than 1 percent of normal have a somewhat milder “later-onset” subtype of the disease. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)

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Diagnosis

Schindler disease may be diagnosed after birth (postnatally) by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Urinary analysis (e.g., oligosaccharide and glycopeptide profiles) may reveal increased levels of certain complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). Reduced activity of the alpha-NAGA enzyme may be confirmed by conducting enzyme tests (assays) on cultured white blood cells (leukocytes), blood plasma, and/or certain skin cells (fibroblasts) from affected individuals.

In children with Schindler disease type I, examination of samples of tissue (biopsy) from the rectum’s mucosal and muscular layers (submucosal and myenteric plexus) may reveal lysosomal accumulation in extensions of nerve cells (axons) of the vegetative (autonomous) nervous system. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) of the brain may reveal degeneration of the outer layer of the brain (cortex), the cerebellum, and the brain stem.

For families with a previous history of Schindler disease, the disorder may be diagnosed before birth (prenatally) by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, tissue samples are removed from a portion of the placenta. Studies performed on these fluid or tissue samples can reveal that there is reduced activity of the alpha-NAGA enzyme.

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Standard Therapies

Treatment

There is no specific therapy for individuals with Schindler disease. The treatment of Schindler disease is directed toward the specific symptoms that are apparent in each individual.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Recently, the crystal structure of human alpha-NAGA has been solved. Analysis of the effect of various mutations identified in patients with Schindler disease type I, II and III permit some prognostic information on a given mutation. Likewise important, those studies identify Schindler disease as a typical protein folding disorder. As such, it might be amenable not only to enzyme replacement therapy, but also pharmacological chaperone approaches.

Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent pathology. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.

Information 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 web site.

For information about clinical trials contact:

www.centerwatch.com, https://clinicaltrials.gov/

Contact for additional information about Schindler disease:

R.J. Desnick, PhD, MD

Dean for Genetic and Genomic Medicine

Professor and Chairman Emeritus,

Dept. of Genetics and Genomic Sciences

Mount Sinai School of Medicine

Phone: 212-659-6700

Fax: 212-360-1809

Email: [email protected]

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References

TEXTBOOKS

Desnick RJ, Schindler D. Schindler Disease: Deficiency alpha-N-acetylgalactosaminidase Activity. In: The Molecular and Genetic Basis of Neurologic and Psychiatric Disease, 4th ed. Rosenberg RN, DiMauro S, Paulson HL, Ptacek L, Nestler EJ, eds. 2008 Lippincott, Williams & Wilkins, Philadelphia, PA. pp. 309-316.

Desnick RJ, Schindler D. Alpha-N-acetylgalactosaminidase Deficiency: Schindler Disease. In: The Molecular and Metabolic Basis of Inherited Disease, 8th ed. Scriver CR, Beaudet AL, Sly WS, et al., eds. 2001 McGraw-Hill, New York, pp.3483-3505.

JOURNAL ARTICLES

Clark NE, Garman SC. The 1.9 a structure of human alpha-N-acetylgalactosaminidase: The molecular basis of Schindler and Kanzaki diseases. J Mol Biol. 2009;435-447.

Westaway SK, Gregory A, Hayflick SJ. Mutations in PLA2G6 and the riddle of Schindler disease. J Med Genet. 2007;44:e64.

Morgan NV, Westaway SK, Morton JEV, et al. PLA2G6, ecoding a phopholipase A, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752-754.

Sakuraba H, Matsuzawa S, Doi H, et al. Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease). J Hum Genet. 2004;49:1-8.

Kodama K, Kobayashi H, Abe R, et al. A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière’s syndrome and without mental retardation. Br J Dermatol. 2001;144:363-368.

Keulemans JL, Reuser AJ, Kroos MA, et al. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J Med Genet. 1996;33:458-464.

Wolfe DE, Schindler D, Desnick RJ. Neuroaxonal dystrophy in infantile alpha-N-acetylgalactosaminidase deficiency. J Neurol Sci. 1995;132:44-56.

Chabás A, Coli MJ, Aparicio M, Rodriquez Diaz E. Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J Inherit Metab Dis. 1994;17:724-731.

Wang AM, Schindler D, Desnick RJ. Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy. J Clin Invest. 1990;86:1752-1756.

Desnick RJ, Wang AW. Schindler disease: an inherited neuroaxonal dystrophy due to alpha-N-acetylgalactosaminidase deficiency. J Inher Metab Dis. 1990;13:549-559.

Schindler D, Bishop DF, Wallace S, et al. Neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. N Engl Med. 1989;320:1735-1740.

INTERNET

Kruer, MC. Lysosomal Storage Disease. Emedicine December 5, 2011. https://emedicine.medscape.com/article/1182830-overview#SchindlerDisease Accessed on:January 31, 2012.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:609241; Last Update:2/7/11 https://omim.org/entry/609241 Accessed on:January 31, 2012.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:609242; Last Update:06/05/2009 https://omim.org/entry/609242 Accessed on:January 31, 2012.

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