Supplement-Direct DNA Testing for Neurogenetic Diseases

By Nancy B. Hanson, MS, Roberta A. Pagon, MD, and Thomas D. Bird, MD

The molecular genetic revolution is having a major impact on the practice of neurology. This phenomenon is especially evident in the area of genetic testing for inherited diseases of the nervous system. The accompanying table lists more than 100 neurological disorders for which a direct DNA test is now commercially available. This table should be of considerable benefit to the busy practicing neurologist who needs quick information concerning the availability of genetic diagnostic testing for the differential diagnosis of specific patients. Metabolic and other non-DNA tests are not listed in this table, but further information about all types of genetic tests can be found at This website provides names and phone numbers of laboratories performing genetic testing as well as research laboratories that may be performing additional tests on a noncommercial (research) basis. A complementary website (www. provides clinical information and guidelines for interpreting and using DNA tests for many of the disorders listed in the table.

Table-Neurologic Diseases with Clinically Available DNA Based Genetic Testing
Disease Name Gene Symbol Gene Locus Gene Product Pattern of Inheritance
Acid Phosphatase Deficiency ACP2 11p12-p11 Lysosomal Acid Phosphatase Autosomal Recessive
ACP3 Chromosome 11
Adenosine Monophosphate Deaminase 1 AMPD1 1p21-p13 AMP Deaminase 1 Autosomal Dominant
Adrenoleukodystrophy, Recessive PEX 10 Autosomal Recessive
PXR1 12p13 Peroxisomal Targeting
Signal 1 Receptor
Adrenoleukodystrophy, X-linked ALD Xq28 Adrenoleukodystrophy protein X-linked
Alpha-Mannosidosis MANB 19cen-q12 Lysosomal Alpha-Mannosidase Autosomal Recessive
Alzheimer Disease, Early Onset Familial PSEN1 14q24 Presenillin 1 Autosomal Dominant
(Presenillin 1)
Amyloidosis Type 1 TTR 18q11-q12 Transthyretin Autosomal Dominant
Amyotrophic Lateral Sclerosis, Familial SOD1 21q22 Superoxide Dismutase (Cu-Zn) Autosomal Dominant
Angelman Syndrome ANCR 15q11-q13 Imprinting
UBE3A 15q11-q13 Ubiquitin-protein ligase E3A Microdeletion
Apert Sydrome FGFR2 10q26 Fibroblast growth factor receptor 2 Autosomal Dominant
Apolipoprotein E Genotyping APOE 19q13 Apolipoprotein E Autosomal Recessive
Ataxia Telangiectasia
Friedreich Ataxia
Spinocerebellar Ataxia Type 1
Spinocerebellar Ataxia Type II
Spinocerebellar Ataxia Type III
Spinocerebellar Ataxia Type VI
Spinocerebellar Ataxia Type VII
Ataxia Telangiectasia ATM 11q22-q23 Autosomal Recessive
Barth Syndrome TAZ Xq28 Tafazzin X-linked
Becker Muscular Dystrophy DMD Xp21 Dystrophin X-linked
Canavan Disease ASPA 17pter-p13 Aspartoacylase Autosomal Recessive
Camitine Deficiency, Systemic SLC22A5 5q31 Autosomal Recessive
Camitine Palmitoyltransferase Deficiency CPT1A 11q Mitochondrial Camitine
Palmitoyltransferase I Autosomal Recessive
CPT2 1p32 Mitochondrial Camitine
Palmitoyltransferase II
Cerebral Autosomal Dominant Arteriopathy with NOTCH3 19p13.2-p13.1 Notch (Drosophila) homolog 3 Autosomal Dominant
Subcortical Infarcts and Leukoencephalopathy
Charcot-Marie-Tooth Disease, Dominant EGR2 (KROX20) 10q21-q22 Early growth response protein 2 Autosomal Dominant
(Type 1) MPZ (CMT1B) 1q22 Myelin PO protein
PMP22 17p11 Peripheral myelin protein 22
Charcot-Marie-Tooth Disease, X-linked GJB1(CX32) Xq13 Gap junction beta-1 protein
(Connexin 32) X-linked
Coffin-Lowry Syndrome RPS6KA3 Xp22 Ribosomal Protein S6
Kinase II Alpha 3 X-linked Dominant
Congenital Hypomyelination Neuropathy (CHN) MPZ 1q22 Myelin PO protein
Congenital Muscular Dystrophy LAMA2 6q22-q23 Laminin Alpha-2 Chain Autosomal Recessive
(Laminin/Merosin type)
Cri du Chat Syndrome 5p deletion Chromosome Deletion
Dentatorubral-Pallidoluysian Atrophy DRPLA 12p13 Atrophin-1 Autosomal Dominant
DiGeorge Syndrome DGCR 22q11 Autosomal Dominant
DGS2 10p14-p13 Microdeletion
Dihydropterin Reductase Deficiency QDPR 4p15 Dihydropteridine Reductase Autosomal Recessive
Duchenne Muscular Dystrophy DMD Xp21 Dystrophin X-linked Recessive
Dystonia Type 1 DYT1 9q34 TorsinA Autosomal Dominant
Dystonia, Dopa Responsive
See GTP Cyclohydrolase Deficiency, Dominant
Emery-Dreifuss Muscular Dystrophy EMD Xq28 Emerin X-linked Recessive
LMNA 1q21 Lamin A Autosomal Dominant
Epidermolysis Bullosa with Muscular Dystrophy PLEC1 8q24 Plectin 1 Autosomal Recessive
Fabry Disease GLA Xq22 Alpha-Galactosidase A X-linked Recessive
Facioscapulohumeral Muscular Dystrophy FSHMD1A 4q35 Autosomal Dominant
Fragile X Syndrome FMR1 Xq27 Fragile X mental
retardation 1 protein X-linked
FRAXE Syndrome FMR2 Xq28 Fragile X mental
retardation 2 protein X-linked Recessive
Friedreich Ataxia FRDA1 9q13 Frataxin Autosomal Recessive
Fructose 1,6 Bisphosphatase Deficiency FBP1 9q22 Fructose-1,6-Bisphosphatase Autosomal Recessive
Fumarate Hydratase Deficiency FH 1q42 Fumarate Hydratase
GTP Cyclohydrolase Deficiency, Dominant GCH1 14q22 GTP Cyclohydrolase I Autosomal Dominant
Gaucher Disease GBA 1q21 Glucosylceramidase Autosomal Recessive
Glycogen Storage Disease Type V (McArdie) PYGM 11q13 Glycogen Phosphorylase,
Muscle Form Autosomal Recessive
Hereditary Fructose Intolerance ALDOB 9q22 Fructose-Bisphosphate
Aldolase B (Liver) Autosomal Recessive
Hereditary Neuropathy with Liability to Pressure PMP22 17p11 Peripheral myelin protein 22 Autosomal Dominant
Palsies (HNPP)
Homocystinuria CBS 21q22 Cystathionine Beta-Synthase Autosomal Recessive
Huntington Disease HD 4p16 Huntington Autosomal Dominant
Hurler Syndrome
See Mucopolysaccaridosis Type I
Hunter Syndrome
See Mucopolysaccaridosis Type II
Hyperkalemic Periodic Paralysis SCN4A 17q23-q25 Sodium Channel Protein,
Skeletal Muscle Autosomal Dominant
Hypokalemic Periodic Paralysis CACNA1S 1q32 Voltage dependent L-type
calcium channel, Autosomal Dominant
alpha-1S subunit
Kallmann Syndrome, X-linked KAL1 Xp22 Kallmann Syndrome Protein X-linked
Kennedy Disease (Spinobulbular AR Xq11-q12 Androgen receptor X-linked
Muscular Atrophy)
KeamsSayre—See Mitochondrial
Krabbe Disease GALC 14q24-q32 Galactocerebrosidase Autosomal Recessive
Langer-Giedion Syndrome LGCR 8q24 Autosomal Dominant
Leber Hereditary Optic Neuropathy
See Mitochondrial
Lesch-Nyhan Syndrome HPRT1 Xq26-q27 Hypoxanthine-Guanine
Phosphoribosyl X-linked
Leigh Disease—See Mitochondrial
Limb-Girdle Muscular Dystrophy
Autosomal Recessive
LGMD 2A CAPN3 15q15-q21 Calpain P94, Large
(Catalytic) Subunit
LGMD 2D SGCA 17q12-q21 Alpha Sarcoglycan
LGMD 2E SGCB 4q12 Beta Sarcoglycan
LGMD 2F SGCD 5q33 Delta Sarcoglycan
Lissencephaly PAFAH1B1 17p13 Platelet-Activating Microdeletion
Factor Acetylhydrolase 1B
Alpha subunit
Long Chain 3-Hydroxyacyl-CoA HADHA 2p23 Mitochondrial Trifunctional
Dehydrogenase Deficiency Enzyme Alpha Subunit Autosomal Recessive
HADHB 2p23 Mitochondrial Trifunctional
Enzyme Beta Subunit
Malignant Hyperthermia Susceptibility CACNA1S 1q32 Autosomal Dominant
MHS2 17q11-q24
MHS2 7q21-q22
MHS4 3q13
MHS6 5p
RYR1 19q13 Ryanodine Receptor,
Skeletal Muscle
McArdie Syndrome
See Glycogen Storage Disease Type V
Medium Chain Acyl-CoA ACADM 1p31 Acyl-CoA Dehydrogenase,
Dehydrogenase Deficiency Medium-Chain Specific Autosomal Recessive
Menkes Disease ATP7A Xq12-q13 Copper-Transporting
ATPase 1 X-linked Recessive
Methylenetetrahydro Folate Reductase MTHFR 1p36 Methylenetetrahydro
Deficiency Folate Reductase Autosomal Recessive
Miller-Dieker Syndrome 17p13 Autosomal Recessive
Mitochondrial Diseases Mitochondrial
Keams-Sayre mitochondrial
Leber Optic Atrophy (LHON) MTND1 mitochondrial NADH-Ubiquinone
Oxidoreductase Chain 1
MTND4 mitochondrial NADH-Ubiquinone
Oxidoreductase Chain 4
MTND6 mitochondrial NADH-Ubiquinone
Oxidoreductase Chain 6
MTCYB mitochondrial Cytochrome B
Leigh Disease MTATP6 mitochondrial ATP Synthase 6
Mitochondrial Myopathy Encephalopathy, MTTL1 mitochondrial Mitochondrial tRNA Leucine 1
Lactic Acidosis and Strokelike Episodes
Myoclonic Epilepsy Associated with Ragged- MTTK mitochondrial Mitochondrial tRNA Lysine
Red Fibers (MERF) MTTL1 mitochondrial Mitochondrial tRNA Leucine 1
Neuropathy, Ataxia, and Retinitis Pigmentosa MTATP6 mitochondrial ATP Synthase 6
Lethal Infantile Mitochondrial Myopathy MTTT mitochondrial Mitochondrial tRNA
Mucopolysaccharidosis Type I (Hurler) IDUA 4p16 Alpha-L-Iduronidase Autosomal Recessive
Mucopolysaccharidosis Type II (Hunter) IDS Xq28 Iduronate 2-Sulfatase X-linked Recessive
Mucopolysaccharidosis Type IIIB (San Filippo) NAGLU 17q21 Alpha-N-
Acetylglucosaminidase Autosomal Recessive
Muscular Dystrophy, see
Becker Muscular Dystrophy
Duchenne Muscular Dystrophy
Limb-Girdle Muscular Dystrophy
Myotonic Dystrophy
Oculopharylgeal Muscular Dystrophy
Myotonia Congenita, Dominant CLCN1 7q35 Chloride Channel Protein,
Skeletal Muscle Autosomal Dominant
SCN4A 17q23-q25 Sodium Channel Protein,
Skeletal Muscle
Myotonia Congenita, Recessive CLCN1 7q35 Chloride Channel Protein,
Skeletal Muscle Autosomal Recessive
Myotonic Dystrophy DMPK 19q13 Myotonin-Protein Kinase Autosomal Dominant
Neurofibromatosis Type 1 NF1 17q11 Neurofibromin Autosomal Dominant
Neurofibromatosis Type II NF2 22q12 Merlin Autosomal Dominant
Neuronal Ceroid Lipofuscinosis, Infantile PPT 1p32 Palmitoyl-Protein Thioesterase Autosomal Recessive
Neuronal Ceroid Lipofuscinosis, Juvenile CLN3 16p12 CLN3 Protein Autosomal Recessive
Neuropathy, Hereditary with Liability to Pressure
Palsies, See HNPP
Niemann-Pick Disease, Type A and B SMPD1 11p15 Sphingomyelin Phosphodiesterase Autosomal Recessive
Niemann-Pick Disease, Type C NPC1 18q11-q12 unknown
Norrie Disease NDP Xp11 Norrie disease protein X-linked
Oculopharyngeal Muscular Dystrophy PABP2 14q11-q13 Polyadenylate-Binding Protein 2 Autosomal Dominant
Omithine Transcarbamylase Deficiency OTC Xp21 Omithine Carbamoyltransferase X-linked Dominant
Pelizaeus-Merzbacher Disease PLP Xq22 Myelin proteolipid protein X-linked
Periodic Paralysis,
See Hyperkalemic and Hypokalemic
Phenylketonuria (PAH Deficiency) PAH 12q24 Phenylalanine-4-Hydroxylase Autosomal Recessive
Prader-Willi Syndrome PWCR 15q11-q13 Imprinting Microdeletion
Pyruvoyl Tetrahydropterin Synthase PTS 11q22-q23 6-Pyruvoyl Tetrahydrobiopterin
Deficiency Synthase Autosomal Recessive
Refsum Syndrome, Adult PHYH 10pter-p11.2 Phytamoyl-CoA Hydroxylase Autosomal Recessive
Rubinstein-Taybi Syndrome CREBBP 16p13 CREB-Binding Protein Autosomal Dominant
San Filippo Syndrome
See Mucopolysaccharidosis Type III
Sandhoff Disease HEXB 5q13 Beta-hexosaminidase beta chain Autosomal Recessive
Smith-Magenis Syndrome SMCR 17p11 Microdeletion
Spinal Muscular Atrophy Types I/II/III NAIP 5q12-q13 Neuronal Apoptosis
Inhibitory Protein Autosomal Recessive
SMN1 5q12-q13 Survival Motor Neuron Protein 1
Spinobulbar Muscular Atrophy
See Kennedy Disease
Spinocerebellar Ataxia Type I SCA1 6p23 Ataxin-1 Autosomal Dominant
Spinocerebellar Ataxia Type II SCA2 12q24 Ataxin-2 Autosomal Dominant
Spinocerebellar Ataxia Type III MJD 14q24-q31 Machado-Joseph Disease Protein 1 Autosomal Dominant
Spinocerebellar Ataxia Type VI CACNA1A 19p13 Autosomal Dominant
Spinocerebellar Ataxia Type VII SCA7 3p21-p12 Autosomal Dominant
Spinocerebellar Ataxia Type VIII SCA8 13q21 Autosomal Dominant
Tay-Sachs Disease HEXA 15q23-q24 Beta-hexosaminidase alpha chain Autosomal Recessive
Tuberous Sclerosis TSC1 9q34 Hamartin Autosomal Dominant
TSC2 16p13 Tuberin
Velocardiofacial Syndrome DGS2 10p14-p13 Autosomal Dominant
VCF 22q11 Microdeletion
Williams Syndrome WBSCR 7q11 Autosomal Dominant
Wolf-Hirschhorn Syndrome WHCR 4p16 Chromosome Deletion
von Hippel-Lindau Syndrome VHL 3p26-p25 von Hippel-Lindau Disease
Tumor Suppressor Autosomal Dominant
Source: GeneTests. January 2000.

Direct DNA testing is a powerful clinical tool that has both risks and benefits.1DNA-based testing directly analyzes disease-causing genes. Therefore, this testing can establish a highly specific diagnosis that may have important prognostic and treatment implications. Test results may also have an important bearing on genetic counseling and estimates of risks to other family members. One example is DNA testing that is now available for many forms of inherited ataxia. It is critical to differentiate Fredreich's ataxia (FA) from the dominant spinocerebellar ataxias, and this can usually be accomplished by DNA testing.2The FA phenotype may overlap that of other ataxias and DNA testing can be highly valuable in establishing the correct diagnosis. This distinction is important because FA typically has an earlier age of onset, an earlier age at death, and increased risk for heart disease and diabetes, and is autosomal recessive compared with the autosomal dominant ataxias.

DNA testing is relatively cost effective compared with other diagnostic laboratory tests. DNA tests typically cost $250-$800. Such tests may also someday be useful in identifying carriers of disease mutations early enough for initiation of therapeutic drugs and treatments. This largely remains a hope for the future, because most neurogenetic disorders have no specific treatments at the present time.

It is worth noting that some DNA-based tests do not identify all possible mutations in a disease gene and other diagnostic tests may also be required. For example, the available DNA test for Duchenne Muscular Dystrophy (DMD) identifies only about 70% of the potential mutations in the DMD gene and a muscle biopsy with straining for dystrophin (the gene product) may be necessary to confirm the diagnosis in some cases.

It is also important to recognize that genetic testing has serious potential risks. A frequent concern is increased stress, anxiety, and depression in individuals receiving a positive test result. This is of particular concern with diseases causing severe progressive disability and reduced lifespan, such as Huntington's disease, familial ALS, and early onset familial Alzheimer's disease.3 Patients need genetic counseling prior to obtaining DNA tests and this is especially true for asymptomatic persons trying to determine if they have inherited a disease mutation.4,5 Patients may have very real concerns regarding possible loss of employment or insurance and most legislatures have not yet come to grips with regulating these issues. The website also has a directory of genetic clinics to help the clinician locate appropriate genetic counseling resources.

Other areas of concern in the use of DNA tests include the testing of children, testing during adoption proceedings, prenatal diagnosis and termination of pregnancy, and use of testing in legal proceedings, such as criminal cases, child custody, and divorce. Guidelines for such situations and the experience of genetic testing centers have been reported and additional experiences will continue to be published.1,4-6

The genetic diagnosis field is moving rapidly and new DNA tests will continue to become available on a regular basis. The table attached to this report and the www. website will be regularly updated. Direct DNA genetic testing provides a remarkable valuable and useful technology that must be combined with caution and good clinical judgment in order to provide the greatest benefit for our patients and their families. —tdb, nbh, rap (Thomas D. Bird, MD, Nancy B. Hanson, MS, and Roberta A. Pagon, MD, Departments of Pediatrics, Medicine, and Neurology, University of Washington, Children's Hospital and Regional Medical Center, and VA Puget Sound Medical Center, Seattle, WA.)


1. Bird TD, et al. Why do DNA testing? Practical and ethical implications of new neurogenetic tests. Ann Neurol 1995; 38:141-146.

2. Mosely ML, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998;51:1666-1671.

3. Almqvist EW, et al. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington Disease. Am J Hum Genet 1999;64:1293-1304.

4. Ragon RA. Genetic diagnosis and counseling in D.C. In: Federman D, Federman E, eds. Scientific American Medicine. Vol VIII. New York, NY: Scientific American Inc; 1999:1-9.

5. Mahowald MB, et al. Genetic counseling: Clinical and ethical challenges. Ann Rev Genet 1998;32:547-559.

6. McKinnon WC, et al. Predisposition genetic testing for late-onset disorders in adults. JAMA 1997;278:1217-1220.