autosomal recessive

Cockayne Syndrome, Type II

Clinical Characteristics

Ocular Features

The eyes are deep-set.  Congenital cataracts are present in 30% of infants.  The aggressive course of this form of CS has precluded full delineation of the ocular features but infants have been described with microphthalmos, microcornea and iris hypoplasia. 

Systemic Features

Evidence of somatic and neurologic delays is present at birth or shortly thereafter with microcephaly and short stature.  Infants never develop normal milestones and may not grow in size beyond that of a 6 month-old child.  Communication skills are minimal.  They have a progeroid appearance, age rapidly, and most do not live beyond 5 years of age.   Feeding problems are common with considerable risk of aspiration, a common cause of respiratory infections and early death.  Severe flexion contractures develop early and may interfere with motor function.  Tremors and weakness contribute as well.  The skin is sensitive to UV radiation in some but not all patients.  However, the frequency of skin cancer is not increased.  Endogenous temperature regulation may be a problem. 

Genetics

This is an autosomal recessive disorder resulting from mutations in ERCC6 (10q11) rendering the excision-repair cross-complementing protein ineffective in correcting defects during DNA replication.  Mutations in this gene account for about 75% of CS patients.  However, using date of onset and clinical severity, type I CS (216400) disease is far more common even though the ERCC8 mutations are found in only 25% of individuals.  Type I CS (216400) also has a somewhat later onset and is less severe in early stages.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation is type III is unknown.

Some patients have combined  phenotypical features of Cockayne syndrome (CS) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

Treatment Options

Feeding tubes may be necessary to maintain nutrition.  Protection from the sun is important.  Physical therapy can be used to minimize contractures.  Cataract surgery might be considered in selected cases as well as assistive devices for hearing problems but the limited lifespan should be considered. 

References

Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A. 2011 May;155(5):1081-95.

PubMed ID: 
21480477

Falik-Zaccai TC, Laskar M, Kfir N, Nasser W, Slor H, Khayat M. Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6. Am J Med Genet A. 2008 Jun 1;146A(11):1423-9.

PubMed ID: 
18446857

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Cockayne Syndrome, Type I

Clinical Characteristics

Ocular Features

A progressive pigmentary retinopathy of a salt-and-pepper type and optic atrophy are commonly seen.  Retinal vessels are often narrowed and older patients can have typical bone spicule formation.  Night blindness, strabismus, and nystagmus may be present as well.  Enophthalmos, hyperopia, poor pupillary responses, and cataracts have been observed.  The lens opacities may in the nucleus or in the posterior subcapsular area and are often present in early childhood.  The ERG is often flat but may show some scotopic and photopic responses which are more marked in older individuals.  Vision loss is progressive but is better than expected in some patients based on the retinal and optic nerve appearance.  The cornea may have evidence of exposure keratitis as many patients sleep with their eyes incompletely closed.  Recurrent corneal erosions have been reported in some patients.

The complete ocular phenotype and its natural history have been difficult to document due to the aggressive nature of this disease.

Ocular histopathology in a single patient (type unknown) revealed widespread pigment dispersion, degeneration of all retinal layers as well as thinning of the choriocapillaris and gliosis of the optic nerve.  Excessive lipofuscin deposition in the RPE was seen.

Systemic Features

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a ‘progeroid’ appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type I is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2nd decade of life but some patients have lived into their 20s.  

Genetics

There is a great deal of clinical heterogeneity in Cockayne syndrome.  Type I results from homozygous or heterozygous mutations in ERCC8 (5q12).  CS type II (133540), is caused by mutations in ERCC6, and has an earlier onset with more rapidly progressive disease.  Both mutations impact excision-repair cross-complementing proteins important for DNA repair during replication.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation in type III is unknown. 

Some patients have combined phenotypical features of Cockayne syndrome (CS) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in nucleotide excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

There may be considerable overlap in clinical features and rate of disease progression among all types.

Treatment Options

No specific treatment is available for Cockayne syndrome.  Supportive care for specific health problems, such as physical therapy for joint contractures, is important. 

Justification of cataract extraction should be made on a case by case basis.  Lagophthalmos requires that corneal lubrication be meticulously maintained.

References

Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A. 2011 May;155(5):1081-95.

PubMed ID: 
21480477

Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol. 1992 Nov 15;114(5):579-83.

PubMed ID: 
1443019

Levin PS, Green WR, Victor DI, MacLean AL. Histopathology of the eye in Cockayne's syndrome. Arch Ophthalmol. 1983 Jul;101(7):1093-7.

PubMed ID: 
6870631

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Fucosidosis

Clinical Characteristics

Ocular Features

Retinal and conjunctival vessels may appear tortuous, dilated, and irregular in diameter, characteristics sometimes seen in Fabry disease.  Diffuse opacities may be seen in the superficial cornea but do not have the whorl-like pattern seen in Fabry disease.  The majority of ocular cells contain cytoplasmic, membrane-bound aggregates of fibrillogranular and multilaminated material.  The orbits may be shallow as a result of bony dysplasia of the cranial bones. 

Systemic Features

The coarse facial features have been described as “Hurler-like”.  Two major types have been described: type 1 with onset in the first 6 months of life and rapid psychomotor and general neurologic deterioration, and the later onset, less severe type 2 in which angiokeratomas resembling Fabry disease occur.  Infants with type 1 may not survive beyond one year of age.  The Hurler-like face is less pronounced and the neurologic deterioration is less rapid in type 2 with survival often into the third decade or later.  The intracellular accumulation of glycolipids and glycoproteins leads to cell death accounting for the progression of CNS disease.   Abnormal bone growth (dysostosis multiplex) can lead to short stature.  Elevated sweat NaCl, hypohidrosis, and poor temperature control can be a feature of both types but this is more pronounced in type 1.  The DNA mutation is the same in both types and there may be overlap in some of the clinical features.  Furthermore, both types have been reported in the same family.

Low levels of alpha-L-fucosidase can be detected in plasma, urine, and leukocytes.  Glycolipids and glycoproteins have also been shown to accumulate in the cells of the skin, liver, spleen, pancreas and kidneys. 

Genetics

Fucosidosis is a rare, progressive, autosomal recessive, lysosomal storage disease in which fucose accumulates in tissue as a result of defective alpha-L-fucosidase.  The responsible mutations are found in the FUCA1 gene (1p34). 

Treatment Options

No treatment is available for the primary disease.  A multidisciplinary supportive program can be beneficial for some patients.  Respiratory therapy especially is important to reduce the threat of infections.

References

Willems PJ, Gatti R, Darby JK, Romeo G, Durand P, Dumon JE, O'Brien JS. Fucosidosis revisited: a review of 77 patients. Am J Med Genet. 1991 Jan;38(1):111-31. Review.

PubMed ID: 
2012122

Hoshino M, O'Brien TP, McDonnell JM, de la Cruz ZC, Green WR. Fucosidosis: ultrastructural study of the eye in an adult. Graefes Arch Clin Exp Ophthalmol. 1989;227(2):162-71.

PubMed ID: 
2721986

Fibrosis of Extraocular Muscles, CFEOM2

Clinical Characteristics

Ocular Features

This is a congenital, autosomal recessive, nonprogressive type of CFEOM which has been described in several consanguineous Middle Eastern families.  The responsible mutations are in a different gene than the one responsible for autosomal dominant CFEOM1 cases although some of the clinical features are similar.  However, in CFEOM2 the eyes are less likely to be infraducted and instead are often fixed in extreme abduction.  In addition, the phenotype is more variable with some eyes fixed in the ‘neutral’ position and others having more mobility than usually seen in CFEOM1 but the clinical heterogeneity is less than that seen in CFEOM3.  Ptosis is part of both phenotypes.  All patients have severe restrictions in ocular motility.  It has been suggested that CEFOM2 patients are likely to have involvement of both superior and inferior divisions of the oculomotor nerve whereas only the superior division is abnormal in CFEOM1.  Binocular vision is absent and amblyopia is common.  The pupils may be small and respond poorly to light. Refractive errors are common.

Based on visual field testing and ERG findings, it has been suggested that subnormal vision in CREOM2 may be due to undescribed retinal dysfunction.  

Systemic Features

Mild facial muscle weakness may be apparent. 

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in the PHOX2A gene at 11q13.3-q13.4.  Another more common form of CFEOM is the autosomal dominant CFEOM1 type (135700) in which the primary fixed deviation is infraduction. The third type is CFEOM3 (600638, 609384) which is clinically more heterogeneous. 

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Treatment Options

Restoration of normal ocular motility is not possible but cosmetic improvement is possible by correcting some of the ptosis with frontalis slings.  Corneal lubrication must be maintained and amblyopia should be treated. 

References

Khan AO, Almutlaq M, Oystreck DT, Engle EC, Abu-Amero K, Bosley T. Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2. Ophthalmic Genet. 2014 Jun 18:1-7. [Epub ahead of print].

PubMed ID: 
24940936

Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet. 2001 Nov;29(3):315-20.

PubMed ID: 
11600883

Wang SM, Zwaan J, Mullaney PB, Jabak MH, Al-Awad A, Beggs AH, Engle EC. Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am J Hum Genet. 1998 Aug;63(2):517-25.

PubMed ID: 
9683611

Nanophthalmos with Retinitis Pigmentosa

Clinical Characteristics

Ocular Features

Poor vision is present beginning in childhood and may progress to hand motion or even loss of light perception when retinal detachments occur.  Nystagmus has been seen in one patient.  Corneal diameters were 11 mm, the angles were open, and axial lengths were shortened to about 17 mm.  Alternating areas of hypo- and hyperfluorescence are seen with fluorescein angiography corresponding to areas with pigment clumping seen throughout the fundi.  The fundus pigmentation is atypical for retinitis pigmentosa, however, in spite of the title given by the authors.  No scotopic or photopic responses are seen on the ERG.  Drusen were present in the optic nerves. 

Systemic Features

No systemic disease is associated. 

Genetics

A single family with affected male and female sibs has been reported and a homozygous nonsense mutation in exon 5 of the CRB1 gene (1q31-32.1) was present in both. 

Another recessive form of microphthalmia with retinitis pigmentosa plus has been reported (611040) without nanophthalmos features and having a mutation in the MFRP gene. True nanophthalmos with retinopathy (267760) has some features similar to the disorder described here but with macular cysts.  No responsible mutation has been identified in this disorder however. 

Treatment Options

Low vision aids might be helpful in early stages of the disease. 

References

Zenteno JC, Buentello-Volante B, Ayala-Ramirez R, Villanueva-Mendoza C. Homozygosity mapping identifies the Crumbs homologue 1 (Crb1) gene as responsible for a recessive syndrome of retinitis pigmentosa and nanophthalmos. Am J Med Genet A. 2011 Apr 11. doi: 10.1002/ajmg.a.33862. [Epub ahead of print]

PubMed ID: 
21484995

Microphthalmia with Retinitis Pigmentosa

Clinical Characteristics

Ocular Features

A decrease in visual acuity with night blindness begins in the third decade of life.  The axial length is decreased resulting in high hyperopia.  There is diffuse scleral thickening, macular schisis of the outer retinal layers, and drusen may be present in the optic nerve.  The retinal pigment epithelium is abnormal with both pigment clumping and bone-spicule formation.  Areas of hypo- and hyperfluorescence are seen on fluorescein angiograms.  The cornea is normal-sized with shallow anterior chambers but narrow angles were not reported.  Intraocular pressures were normal.  On ERG recordings rod responses are missing while cone tracings are severely diminished. 

Systemic Features

No systemic disease is associated. 

Genetics

Based on consanguinity in the parents of the single family reported, this seems to be an autosomal recessive disorder.  Molecular studies confirm that the four affected sibs are homozygous for mutations in the MFRP gene (11q23) while the parents are both heterozygous.

Another disorder of small eyes but with classical findings of nanophthalmos and retinitis pigmentosa has also been described (267760) (nanophthalmos with retinopathy) and may be the same disorder especially since no molecular mutation has been identified.  

Treatment Options

Low vision aids may be helpful, at least in early stages of the disease. 

References

Ayala-Ramirez R, Graue-Wiechers F, Robredo V, Amato-Almanza M, Horta-Diez I, Zenteno JC. A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation. Mol Vis. 2006 Dec 4;12:1483-9.

PubMed ID: 
17167404

Ablepharon-Macrostomia Syndrome

Clinical Characteristics

Ocular Features

The clinical features of this syndrome remain to be fully delineated.  Important ocular anomalies include malformations and sometimes absence of the upper and lower eyelids.  The eyelashes and eyebrows may be sparse or even missing.  The lid fissures, if present, may be shortened.  Deformities of the eyelids can lead to corneal exposure and secondary vision loss. 

Systemic Features

Other facial malformations include macrostomia which may be secondary to aberrant lip fusion.  Micrognathia has been described.  The external ears are often rudimentary, sometimes described as rosebuds.  The nasal bridge is low and the nostrils anteverted.  The zygomatic arches may be absent.  The nipples are often missing as well.  Scalp hair is sparse or even absent while the skin is dry, coarse, and often has redundant folds (cutis laxa).  Mild skin syndactyly, camptodactyly, finger contractures, and shortening of metacarpals have been noted.  The genitalia are often ambiguous and some patients have had ventral hernias.  Hearing loss can be a feature.  Growth retardation has been seen but developmental delays if present are mild.  Intelligence can be normal. 

Genetics

The majority of sibships suggest autosomal recessive inheritance although autosomal dominant inheritance has been proposed for several. One male child has been reported to have a partial deletion of chromosome 18 but other complex rearrangements were also present. 

Treatment Options

Cosmetic surgery can correct at least some of the malformations. Vigorous effort may be required to maintain corneal surface wetting. 

References

Rohena L, Kuehn D, Marchegiani S, Higginson JD. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am J Med Genet A. 2011 Apr;155(4):850-4.

PubMed ID: 
21595001

Stevens CA, Sargent LA. Ablepharon-macrostomia syndrome. Am J Med Genet. 2002 Jan 1;107(1):30-7.

PubMed ID: 
11807864

Cruz AA, Souza CA, Ferraz VE, Monteiro CA, Martins FA. Familial occurrence of ablepharon macrostomia syndrome: eyelid structure and surgical considerations. Arch Ophthalmol. 2000 Mar;118(3):428-30.

PubMed ID: 
10721975

Ferraz VE, Melo DG, Hansing SE, Cruz AA, Pina-Neto JM. Ablepharon-macrostomia syndrome: first report of familial occurrence. Am J Med Genet. 2000 Oct 2;94(4):281-3.

PubMed ID: 
11038439

Adrenoleukodystrophy, Autosomal

Clinical Characteristics

Ocular Features

This early onset and rapidly progressive form of adrenoleukodystrophy is rare.  The early onset and rapidly fatal course of the disease has limited full delineation of the ocular features.  The most striking is the presence of ‘leopard-spots’ pigmentary changes in the retina.  Polar cataracts, strabismus, and epicanthal folds have also been reported. 

Systemic Features

Onset of symptoms occurs shortly after birth often with seizures and evidence of psychomotor deficits.  Rapid neurologic deterioration begins at about 1 year of age with death usually by the age of 3 years.  Hyperpigmentation of the skin may be apparent a few months after birth.  Opisthotonus has been observed.  The ears may be low-set, the palate is highly arched, and the nostrils anteverted.  Frontal bossing may be present.  Serum pipecolic acid and very-long-chain fatty acids (VLCFAs) can be markedly elevated.  Cystic changes in the kidneys have been reported. 

Genetics

This is an autosomal recessive peroxismal disorder resulting from homozygous mutations in receptor gene mutations such as PEX1, PEX5, PEX13, and PEX26.

There is also an X-linked recessive adrenoleukodystrophy (300100) sometimes called ALD but it lacks some of the morphologic features and is somewhat less aggressive. 

Neonatal adrenoleukodystrophy along with infantile Refsum disease (266510, 601539) and Zellweger syndrome (214100) are now classified as Zellweger spectrum or perioxismal biogenesis disorders.

Treatment Options

Treatment is mainly supportive for associated health problems. 

References

Chen WW, Watkins PA, Osumi T, Hashimoto T, Moser HW. Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy. Proc Natl AcadSci U S A. 1987 Mar;84(5):1425-8.

PubMed ID: 
3469675

Cohen SM, Green WR, de la Cruz ZC, Brown FR 3rd, Moser HW, Luckenbach MW, Dove DJ, Maumenee IH. Ocular histopathologic studies of neonatal and childhood adrenoleukodystrophy. Am J Ophthalmol. 1983 Jan;95(1):82-96.

PubMed ID: 
6295171

Neuraminidase Deficiency

Clinical Characteristics

Ocular Features

A cherry red spot is may be seen in late childhood or early adolescence.  It occurs in nearly 100% of patients with type I while only 75% of type II patients have this feature possibly because their early death from the more severe systemic disease prevents full ascertainment.  Visual acuity is reduced, sometimes severely.  Some but not all individuals have corneal and lens opacities.  A subtle corneal haze has also been seen.  Nystagmus has been reported. 

Systemic Features

This is a neurodegenerative disorder with progressive deterioration of muscle and central nervous system functions.  Myoclonus, mental deterioration, hepatosplenomegaly, muscle weakness and atrophy are common.  The defect in neuraminidase activity leads to abnormal amounts of sialyl-oligosaccharides in the urine.  Spinal deformities such as kyphosis are common.  Deep tendon reflexes are exaggerated.  Ataxia and hearing loss may be present.  Coarse facies, a barrel chest, and short stature are characteristic.  Hepatic cells contain numerous vacuoles and numerous inclusions.

Sialidosis types I and II are both caused by mutations in the neuroaminidase gene.  Type I is associated with milder disease than type II which has an earlier age of onset and may present in infancy or even begin in utero.  Early death within two years of age is common in the congenital or infantile forms.  There is, however, significant variability in age of onset and the course of disease among types. 

Genetics

The sialidoses are autosomal recessive lysosomal storage disorders resulting from mutations in the NEU1 gene (6p21.3) which lead to an intracellular accumulation of glycoproteins containing sialic acid residues.  Both types I and II are caused by mutations in the same gene. 

Treatment Options

Treatment is focused on symptom management. 

References

Heroman JW, Rychwalski P, Barr CC. Cherry red spot in sialidosis (mucolipidosis type I). Arch Ophthalmol. 2008 Feb;126(2):270-1.

PubMed ID: 
18268224

Goldberg MF. Macular cherry-red spot and corneal haze in sialidosis (mucolipidosis type 1). Arch Ophthalmol. 2008 Dec;126(12):1778; author reply 1778.

PubMed ID: 
19064869

Federico A, Cecio A, Battini GA, Michalski JC, Strecker G, Guazzi GC. Macular cherry-red spot and myoclonus syndrome. Juvenile form of sialidosis. J Neurol Sci. 1980 Nov;48(2):157-69.

PubMed ID: 
7431038

Sandhoff Disease

Clinical Characteristics

Ocular Features

Retinal ganglion cells become dysfunctional as a result of the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Treatment Options

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References

Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL. Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet. 2002 May 15;11(11):1343-50.

PubMed ID: 
12019216

Neufeld EF. Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase. J Biol Chem. 1989 Jul 5;264(19):10927-30. Review.

PubMed ID: 
2525553

Gilbert F, Kucherlapati R, Creagan RP, Murnane MJ, Darlington GJ, Ruddle FH. Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes. Proc Natl Acad Sci U S A. 1975 Jan;72(1):263-7.

PubMed ID: 
1054503