DiagnosisClinical DiagnosisThe diagnosis of childhood ataxia with central nervous system hypomyelination/leukoencephalopathy with vanishing white matter (CACH/VWM) can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial MRI [van der Knaap et al 2006], and identifiable mutations in one of the five genes in which mutation is causative (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5), encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B) [Leegwater et al 2001, van der Knaap et al 2002]. Clinical findings Antenatal/early-infantile forms are characterized by severe encephalopathy; oligohydramnios, intrauterine growth retardation, microcephaly, contractures, cataract, pancreatitis, hepatosplenomegaly, and renal hypoplasia may be present. In all later onset forms initial motor and intellectual development is normal or mildly delayed. Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma. Clinical examination usually shows a combination of truncal and appendicular ataxia and spasticity with increased tendon reflexes. The peripheral nervous system is usually not involved. Optic atrophy may develop. Epilepsy may occur but is not the predominant sign of the disease except in an acute situation. Intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult onset forms. Ovarian dysgenesis may be present as primary or secondary amenorrhea [Fogli et al 2003]. MRI findings The cerebral hemispheric white matter is symmetrically and diffusely abnormal. The abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid (CSF) on T₁-weighted (Figure 1), T₂-weighted (Figure 2), and fluid-attenuated inversion recovery (FLAIR) (Figure 3) images. On T₁-weighted and FLAIR images, a fine meshwork of remaining tissue strands is usually visible within the areas of CSF-like white matter, with a typical radiating appearance on sagittal and coronal images and a dot-like pattern in the centrum semiovale on the transverse images (Figure 4) [van der Knaap et al 2002, van der Knaap et al 2006]. The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic at-risk sibs of a proband. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [van der Knaap et al 2006]. Cerebellar atrophy varies from mild to severe and primarily involves the vermis. Supratentorial cortico-subcortical atrophy can be observed in adult onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.FigureMRI of an individual with the classic form of CACH
Figure 1. Diffuse hypointensity of the white matter on T₁-weighted images
Figure 2. Increased signal intensity in the same white matter area on T₂-weighted images
Figure 3. Secondary (more...)FigureFigure 4. Parasagittal T₁-weighted MRI image of an individual with CACH shows diffuse hypointensity of the white matter interrupted by a typical meshwork of remaining tissue strands radiating across the abnormal white matter. TestingRoutine laboratory tests, including CSF analysis, are normal. Research testingEukaryotic translation initiation factor 2B (eIF2B) guanine exchange factor (GEF) activity measured in lymphoblastoid cell lines from affected individuals was found to be lower in most persons with mutations in EIF2B1 through EIF2B5 than in control subjects [Fogli et al 2004b]. eIF2B GEF activity assays in lymphoblastoid cell lines from 63 affected persons presenting with different clinical forms and EIF2B mutations showed a significantly decreased GEF activity in cells from EIF2B mutated individuals with 100% specificity and 89% sensitivity when the activity threshold was set at 77.5% of normal [Horzinski et al 2009]. In the early infantile form of the disease (onset age <3 years) the GEF activity was below the threshold of 77.5% of normal. Persons with late onset disease and a wide variety of mutations (Table 1) had higher GEF activity that overlapped with the normal range. A significant decrease of GEF activity has also been reported in the 8/8 EIF2B -mutated lymphoblastoid cell lines and 3/4 fibroblast cell lines analyzed by Liu et al [2011]. However, no correlation between eIF2B GEF activity and disease severity was found in this study. The findings were substantiated by similar results in transfected HEK293 cells [Liu et al 2011]. Thus it can be concluded that if decreased activity is found, CACH/VWM is the most likely diagnosis; but if normal or increased activity is found, CACH/VWM cannot be ruled out.The CSF asialotransferrin/total transferrin ratio was found to be low in persons with genetically confirmed CACH/VWM, a finding that can help identify those likely to have mutations in any of the five genes encoding the eIF2B subunits detected on sequence analysis. Note: This test is cumbersome and may not be generally available. Molecular Genetic TestingGenes. The five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) that encode the five subunits of the eukaryotic translation initiation factor eIF2B are the genes in which mutations are known to cause CACH/VWM. In an affected individual both alleles are mutated in any one of the involved genes.Evidence for locus heterogeneity. Approximately 10% of families with CACH/VWM diagnosed by MRI and clinical criteria do not have an identifiable mutation on sequence analysis of EIF2B1- EIF2B5, suggesting the possibility of causative mutations in other genes.Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White MatterView in own windowGene SymbolProportion of CACH/VWM Attributed to Mutations in This Gene ^{1Test MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 2 Test AvailabilityEIF2B1 2%Sequence analysisSequence variants 3See footnotes 1, 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6EIF2B213.6%Sequence analysisSequence variants 3See footnotes 1, 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6EIF2B39.1%Sequence analysisSequence variants 3See footnotes 1, 4Clinical Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6EIF2B410.6%Sequence analysisSequence variants 3See footnotes 1, 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6EIF2B564.7%Sequence analysisSequence variants 3See footnotes 1, 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6Targeted mutation analysisc.338G>A, c.584G>A100% for the targeted variants 71. In individuals with MRI-confirmed CACH/VWM, mutation detection frequency for all five genes together is ~90% by sequence analysis/mutation scanning [Leegwater et al 2001, van der Knaap et al 2002, van der Knaap et al 2003, Fogli et al 2004a, Ohtake et al 2004, Ohlenbusch et al 2005, Vermeulen et al 2005, Federico et al 2006, Fogli & Boespflug-Tanguy 2006, Kaczorowska et al 2006, Mierzewska et al 2006, Pronk et al 2006, Ramaswamy et al 2006, Scali et al 2006, Denier et al 2007, Huntsman et al 2007, Matsui et al 2007, Passemard et al 2007, Riecker et al 2007, Damon-Perriere et al 2008, Fontenelle et al 2008, Horzinski et al 2008, Jansen et al 2008, Maletkovic et al 2008, Mathis et al 2008, Peter et al 2008, Pineda et al 2008, Labauge et al 2009, Wu et al 2009]. 2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.4. Approximately 90% of mutations are missense [Fogli et al 2004a]. Affected individuals are homozygotes or compound heterozygotes for mutations within the same gene. Mutations have been found in affected individuals of all ethnic origins [Leegwater et al 2001, Fogli et al 2002b, van der Knaap et al 2002, Fogli et al 2004a]. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. No deletions or duplications involving EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5 have been reported as causative of CACH/VWM. Therefore, the mutation detection rate is unknown and may be very low. 7. Targeted mutations may vary by laboratory. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm the diagnosis in a probandSingle gene testingMolecular genetic testing (in order) of EIF2B5, EIF2B2, EIF2B4, EIFB3, and EIF2B1 is recommended. Sequencing of the coding sequence and associated splice sites must be performed. Deletion/duplication analysis would also be useful to perform particularly in individuals with clinical CACH/VWM in whom direct sequencing has failed to identify mutations.Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CACH/VWM is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersThus far, all individuals with eIF2B-related disease have a leukodystrophy; no other phenotypes have been observed.}

Natural HistoryChildhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) phenotypes range from a congenital or early infantile form to a subacute infantile form (onset age <1 year), an early childhood onset form (onset age 1-5 years), a late childhood/juvenile onset form (onset age 5-15 years), and an adult onset form [Fogli & Boespflug-Tanguy 2006]. Both the childhood and juvenile forms have been observed in sibs [Leegwater et al 2001]; the infantile and juvenile/adult forms have never been observed within the same family. Neurology. The neurologic signs include ataxia, spasticity, and variable optic atrophy. In the early onset forms, the encephalopathy is severe, seizures are often a predominant clinical feature and decline is rapid and followed quickly by death; in the later onset forms, decline is usually slower and milder [van der Knaap et al 2002]. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illness or following minor head trauma or fright [Vermeulen et al 2005, Kaczorowska et al 2006]. Ovarian failure. While the juvenile and adult forms are often associated with primary or secondary ovarian failure, a syndrome referred to as "ovarioleukodystrophy" [Schiffmann et al 1997, Fogli et al 2003], ovarian dysgenesis may occur in any of the forms regardless of age of onset [van der Knaap et al 2003]; it has been found at autopsy in infantile and childhood cases. Because the affected individuals were prepubertal, the ovarian dysgenesis was clinically not manifest. Antenatal form. The antenatal onset form presents in the third trimester of pregnancy with oligohydramnios and decreased fetal movement [van der Knaap et al 2003]. Clinical features that may be noted soon after birth include feeding difficulties, vomiting, hypotonia, mild contractures, and cataract (sometimes oil droplet cataract) and microcephaly. Apathy, intractable seizures, and finally apneic spells and coma follow. Other organ involvement can include hepatosplenomegaly, renal hypoplasia, pancreatitis, and ovarian dysgenesis. The clinical course is rapidly and relentlessly downhill; the adverse effect of stress factors is less clear. So far, all infants with neonatal presentation have died within the first year of life [van der Knaap et al 2003]. Infantile form. A rapidly fatal severe form of CACH/VWM is characterized by onset in the first year of life and death a few months later [Francalanci et al 2001, Fogli et al 2002a, Fogli et al 2002b]. Two sisters described by Francalanci et al [2001] developed irritability, stupor, and rapid loss of motor abilities following an intercurrent infection at age ten to 11 months and died at age 21 months. Another infantile-onset phenotype was described as "Cree leukoencephalopathy" because of its occurrence in the native North American Cree and Chippewayan indigenous population [Fogli et al 2002b]. Infants typically have hypotonia followed by sudden onset of seizures (age 3-6 months), spasticity, rapid breathing, vomiting (often with fever), developmental regression, blindness, lethargy, and cessation of head growth, with death by age two years. Early childhood onset form. Initially most children develop normally; some have mild motor or speech delay. New-onset ataxia is the most common initial symptom between ages one and five years. Some children develop dysmetric tremor or become comatose spontaneously or acutely following mild head trauma or febrile illness [Schiffmann et al 1994, van der Knaap et al 1997]. Subsequently, generally progressive deterioration results in increasing difficulty in walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a child becomes nonambulatory, the clinical course may remain stable for several years. Swallowing difficulties and optic atrophy develop late in the disease.Head circumference is usually normal; however, severe progressive megalencephaly occurring after age two years has been reported [Passemard et al 2007]; microcephaly has also been observed. The peripheral nervous system is usually normal, although predominantly sensory nerve involvement has been reported in recent cases [Federico et al 2006, Huntsman et al 2007]. Intellectual abilities are relatively preserved.The time course of disease progression varies from individual to individual even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring many years after onset.Late childhood/juvenile onset form. Children develop symptoms between ages five and 15 years. They often have a more slowly progressive spastic diplegia, relative sparing of cognitive ability, and likely long-term survival with long periods of stability and even improvement of motor function [Schiffmann et al 1994, van der Knaap et al 1998]. However, rapid progression and death after a few months have also been described [van der Knaap et al 1998]. Adult onset form. Behavioral problems associated with cognitive decline are frequently reported before neurologic symptoms appear [Labauge et al 2009]. Acute, transient neurologic symptoms (optic neuritis, hemiparesis) or severe headache, as well as primary or secondary amenorrhea in females, can be the presenting symptoms. Asymptomatic and symptomatic adults with two mutations in one of the genes and a typically affected sibling have also been described [Leegwater et al 2001, Biancheri et al 2003, Ohtake et al 2004, van der Knaap et al 2004].Neuropathologic findings in general are a "cavitating orthochromatic leukodystrophy with rarity of myelin breakdown and relative sparing of axons” [Fogli et al 2002b]. Vacuolation and cavitation of the white matter are diffuse, giving a spongiform appearance. Cerebral and cerebellar myelin is markedly diminished, whereas the spinal cord is relatively spared. Oligodendrocytes are increased in number [Rodriguez et al 1999, van Haren et al 2004], whereas astrocytes are decreased, especially in the severe infantile form [Francalanci et al 2001]. The hallmark is the presence of oligodendrocytes with "foamy" cytoplasm and markedly hypotrophic and sometimes atypical astrocytes [Wong et al 2000]. The white matter astrocytes and oligodendrocytes are immature and are, in fact, astrocyte and oligodendrocyte precursor cells, explaining the lack of myelin production and scarce gliosis [Bugiani et al 2011].

Genotype-Phenotype CorrelationsAlthough intrafamilial variability exists, correlation between certain homozygous mutations and age of onset and disease severity has been described [Fogli et al 2004a, van der Lei et al 2010]:In individuals homozygous for the p.Thr91Ala mutation in EIF2B5, the phenotype may vary from childhood onset to adults with no symptoms [Leegwater et al 2001]. The neonatal onset form is characterized by a more diffuse encephalopathy with failure of development and serious seizures [van der Knaap et al 2003]. Certain EIF2B5 homozygous mutations, such as p.Arg113His, never give rise to the infantile type [Fogli et al 2004a]. Certain EIF2B5 mutations, such as p.Val309Leu, are predictably associated with severe disease [Fogli et al 2004a].

Differential DiagnosisOther disorders affecting the white matter diffusely during childhood to consider, with their distinguishing MRI findings:X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and Canavan disease. In the cerebral form of X-linked adrenoleukodystrophy and the other three disorders, MRI shows extensive or diffuse cerebral white matter changes but as a rule no cystic degeneration. Alexander disease. In this condition white matter signal changes have a frontal predominance. The cystic degeneration may affect the subcortical or deep white matter. Basal ganglia and thalamic abnormalities are frequently present. Contrast enhancement of characteristic structures often facilitates the diagnosis. The diagnosis can be established with molecular genetic testing. Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by diffusely abnormal and mildly swollen cerebral hemispheric white matter that does not show signs of diffuse rarefaction or cystic degeneration. Subcortical cysts are almost always present in the anterior temporal area and often in other regions. The cysts are best seen on proton density and FLAIR. The diagnosis can usually be established with molecular genetic testing. Mitochondrial disorders, including deficiencies of pyruvate dehydrogenase and pyruvate carboxylase. MRI abnormalities similar to those seen in CACH/VWM with prominent and diffuse white matter rarefaction and cystic degeneration may be seen in mitochondrial disorders [DeLonlay-Debeney et al 2000].PLP1-related disorders (Pelizaeus Merzbacher disease and X-linked spastic paraplegia type 2). Diffuse hyperintensity of the white matter on T₂-weighted images is also observed in leukodystrophies with primary hypomyelination, such as the PLP1-related disorders; however, these disorders have a normal or nearly normal white matter signal on T₁-weighted images and CT scan. In addition, central nerve conduction evaluated with evoked potentials is always severely affected even at an early stage of the disease. CADASIL, lamin B1 mutations, or acquired white matter disorders such as multiple sclerosis need to be considered in individuals with adult-onset CACH/VWM; however, the early, constant, diffuse, symmetric alteration of the white matter on MRI in eIF2B-related disorders is distinctive. Further studies are needed to determine if white matter disorders described as orthochromatic leukodystrophies are related to CACH/VWM.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CACH/VWM, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Infantile formEarly childhood onset formLate childhood/juvenile onset formAdult onset form

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), the following evaluations are recommended:Brain MRI Ophthalmologic examination Neurologic examination Physical therapy/occupational therapy assessment as needed Medical genetics consultationTreatment of ManifestationsThe following are appropriate:Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia) Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors Antiepileptic drugs for treatment of seizures and abnormalities of behavior and mood Prevention of Secondary ComplicationsConsidering the known adverse effect of fever, it is important to prevent infections and fever as much as possible (e.g., through the use of vaccinations, including anti-flu vaccination); low-dose maintenance antibiotics during winter time, antibiotics for minor infections, and antipyretics for fever are appropriate. For children, wearing a helmet outside helps minimize the effects of possible head trauma.SurveillanceClose surveillance for several days following head trauma or major surgical procedure with anesthesia is indicated because neurologic deterioration (presumably stress related) may follow.Agents/Circumstances to AvoidAvoid the following:Contact sports and other activities with a high risk of head traumaStressful emotional and physical situations (e.g., extreme temperatures)Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherIn general, corticosteriods and intravenous gamma globulin are not effective in the treatment of CACH/VWM. Corticosteriods have been used with inconsistent results in acute situations, including intractable status epilepticus.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEIF2B214q24​.3Translation initiation factor eIF-2B subunit betaEIF2B2 homepage - Mendelian genesEIF2B2EIF2B31p34​.1Translation initiation factor eIF-2B subunit gammaEIF2B3 homepage - Mendelian genesEIF2B3EIF2B42p23​.3Translation initiation factor eIF-2B subunit deltaEIF2B4 homepage - Mendelian genesEIF2B4EIF2B53q27​.1Translation initiation factor eIF-2B subunit epsilonEIF2B5 homepage - Mendelian genesEIF2B5EIF2B112q24​.31Translation initiation factor eIF-2B subunit alphaEIF2B1 homepage - Mendelian genesEIF2B1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter (View All in OMIM) View in own window 603896LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER; VWM 603945EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 5; EIF2B5 606273EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 3; EIF2B3 606454EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 2; EIF2B2 606686EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 1; EIF2B1 606687EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 4; EIF2B4Molecular Genetic PathogenesisThe eukaryotic translation initiation factor eIF2B is composed of five subunits. Its function is to convert protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex, allowing the formation of the 43S complex, precursor of protein translation initiation. It is not yet understood why a defect in eIF2B, a ubiquitous protein complex, affects predominantly the brain white matter. The crucial role of eIF2B as regulator of protein synthesis under stress conditions could explain the neurologic deterioration during or after head trauma and fever [Leegwater et al 2001]. Yeast with null mutations for any of the five genes EIF2B1-EIF2B5 are not viable. Mutations that completely abolish eIF2B activity are probably lethal in the homozygous state in humans; this explains why nonsense mutations are rare and only observed in compound heterozygotes in association with a missense mutation [Leegwater et al 2001, Fogli et al 2002b, van der Knaap et al 2002]. Mutations in EIF2B1-EIF2B5 were shown to decrease the guanine exchange factor (GEF) activity in vitro in yeast and mammalian cellular models. This reduction in activity results from aberrant protein folding, leading to an impaired ability to form functional eIF2B complexes that bind substrate normally [Li et al 2004, Richardson et al 2004, van Kollenburg et al 2006a]. The decrease in GEF activity leads to enhanced translation of specific mRNA of proteins, similar to the situation that occurs when a cell is under stress. Decreased GEF activity of 20%-77% of normal was also found in lymphoblasts of most affected individuals but was normal in obligate heterozygotes [Fogli et al 2004b, Horzinski et al 2009] and some patients [Horzinski et al 2009, Liu et al 2011]. Hyper-induction of ATF4-mediated ER-stress response is variably found in eIF2B-mutated cells [Kantor et al 2005, Kantor et al 2008, Horzinski et al 2010] or brain [van der Voorn et al 2005, van Kollenburg et al 2006b]. Normal allelic variants. See Table 2 (pdf) for exon number and cDNA length of each gene. Pathologic allelic variants. See Table 3 (pdf) for a listing and frequency of selected pathologic allelic variants of each gene. Table 4. Selected EIF2B5 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.271A>Gp.Thr91AlaNM_003907​.2
NP_003898​.2c.338G>Ap.Arg113Hisc.584G>Ap.Arg195Hisc.925G>Cp.Val309LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. See Table 5 (pdf) for a description of protein subunits.Abnormal gene product. See Molecular Genetic Pathogenesis.