cherry red spot

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
Treatment Options: 

Treatment is focused on symptom management. 

References
Article Title: 

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from 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. 

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Tay-Sachs 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: 

Sandoff 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 hexosaminidase enzyme).   The infantile form of this lysosomal storage disease is the most common.  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.  The facies are coarse and the tongue is enlarged.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Hepatosplenomegaly is usually not present.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.     

Ataxia with spinocerebellar degeneration, motor neuron disease, 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

Tay-Sachs disease is an autosomal recessive disorder caused by mutations in the hexosaminidase A gene, HEXA, (15q23-q24).  The altered enzyme is unable to break down GM2 ganglioside which accumulates in lysosomes and leads to neuronal death.

A related form, clinically and biochemically similar to Tay-Sachs disease , is GM2-gangliosidosis (272750) but it is caused by mutations in GM2A (5q31.3-q33.1) with normal hexosaminidase A and B.  Sandhoff disease (268800) is clinically indistinguishable but caused by mutations in the beta subunit of hexosaminidase (HEXB) A and B at 5q13. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely supportive.  Anticonvulsant pharmaceuticals may help in the control of seizures but require frequent modifications as the neuronal degeneration progresses.  Airways and nutrition maintainence are important.

Application of gene therapy to cell cultures have shown promise in restoring enzyme function and may someday lead to human treatment. 

    

References
Article Title: 

Tay-Sachs disease

Fernandes Filho JA, Shapiro BE. Tay-Sachs disease. Arch Neurol. 2004 Sep;61(9):1466-8. Review.

PubMed ID: 
15364698

Niemann-Pick Disease, Types C1 (D)

Clinical Characteristics
Ocular Features: 

The predominant ocular sign in types C1 is difficulty in upgaze described as a supranuclear palsy.  Abnormal saccadic movements have been reported as well.  Retinal signs such as a cherry red spot are not common.

Systemic Features: 

Hepatosplenomegaly and cognitive decline are similar in nature to those found in Niemann-Pick disease types A and B.  Types C1 and C2 are clinically similar but discussed separately as they are caused by mutations in separate genes.  Type D is caused by the same mutation causing C1.  Onset of disease manifested by ataxia, seizures and spasticity is usually between 2 and 4 years.  Dystonia, intention tremor, dysarthria, and hepatosplenomegaly are other features but visceral involvement may be absent.  Ascites and jaundice are sometimes present.  Dementia and extrapyramidal signs are often seen later.  However, there is considerable variation in onset and progression of disease but the symptoms are generally milder than that in types A and B.

Genetics

Type C1 (and D) are caused by mutations in the NPC1 gene (18q11-q12), and type C2 (607625) by mutations in the NPC2 gene (14q24.3).  Mutations in C1 are far more common (95%) than C2 mutations.  The gene mutations reduce the efficiency of sphingosine efflux from lysosomes and late endosomes as a result of a defect in esterification of cholesterol.

Types A (257200) and B (607616) Niemann-Pick disease generally cause more severe clinical signs and are the result of a sphingomyelinase deficiency.  All types of Niemann-Pick disease follow autosomal recessive patterns of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has recently been reported that intrathecal 2-hydroxypropyl-beta-cyclodextrin slows progression of clinical symptoms and prolonged lifespan.

References
Article Title: 

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-v-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Aug 10. pii: S0140-6736(17)31465-4. doi: 10.1016/S0140-6736(17)31465-4. [Epub ahead of print].

PubMed ID: 
28803710

Niemann-Pick disease type C

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. Review.

PubMed ID: 
12974729

Niemann-Pick Disease, Types A and B

Clinical Characteristics
Ocular Features: 

Affected infants usually develop prominent cherry red spots during the first 12 months of life and the entire retina has an ‘opaque’ appearance.  Intracellular lipid accumulation has been seen in retinal neurons, amacrine cells, retinal pigment epithelial cells, and receptors.  The cornea has stromal haziness.  The lens has a brownish coloration on the anterior surface with white spots on the posterior capsule.  Lens opacification seems to progress.

Vision in the first year of life is likely normal as infants have normal fixation, pupillary reactions, and following movements with no nystagmus.  However, by about 2 years of age visual responsiveness may be lost.

Systemic Features: 

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.

Genetics

This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1.  This recessive gene has an unusual biology.  Only the maternally inherited allele is active in the homozygous condition.  Such parent-specific gene activation is called gene imprinting.

Types A and B are allelic disorders.  

Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625)  from mutations in the NPC2 gene (14q24.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy trials are underway.  Amniotic membrane, bone marrow, and stem cell transplantation have been tried with some improvement in visceral disease but the results are mixed and await further studies.

References
Article Title: 

Krabbe Disease

Clinical Characteristics
Ocular Features: 

Subtle cherry red spots have been reported in one patient.  More than half (53%) have abnormal VEP response but the ERG is normal.  Optic atrophy with blindness is not uncommon but the full ocular phenotype remains unknown.  A 6-month-old male child had MRI T2 evidence of intracranial optic nerve hypertrophy which was attributed to an accumulation of globoid cells.

Systemic Features: 

There is considerable variation in the time of onset and rate of progression in Krabbe disease, even within families.  Patients with infantile disease may present with symptoms at about 6 months of life, while others are not diagnosed until late childhood or adolescence.  Some evidence of psychomotor retardation is often the first sign of disease with ataxia and limb spasticity soon following.  Irritability is an early sign.  Neurophysiologic studies often show abnormal nerve conduction and this has been documented even in newborns.  The disorder is one of progressive neurodegeneration of both central and peripheral nervous systems leading to weakness, seizures and loss of protective reflexes.  The MRI may reveal T2 hyperintensity in cerebral and cerebellar white matter, internal capsules and pyramidal tracts.  Infection and respiratory failure are responsible for most deaths.

The life-span of Infants with Krabbe disease is approximately one year while those with late-onset disease may not develop symptoms until almost any age and the clinical course is highly variable.

Genetics

This is an autosomal recessive disorder secondary to mutations in the GALC gene (14q31) encoding the enzyme galactosylceramidase, important in the growth and maintenance of myelin.

One patient has been reported with ‘atypical’ Krabbe disease (611722) secondary to a homozygous mutation in the PSAP gene (10q22.1).  The infant had a deficiency of saposin A as well as decreased galactocerebrosidase activity in white blood cells

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Normal blood galactocerebrosidase can be restored and CNS deterioration may be delayed or improved with transplantation of allogeneic hematopoietic stem cells or umbilical cord blood.   However, some patients have residual language deficits and mild to severe delays in motor function.  Results are better if treatment is commenced during infancy before development of symptoms.  These treatments are experimental and long range outcomes remain uncertain.

References
Article Title: 
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