dementia

Neurodegeneration with Brain Iron Accumulation

Clinical Characteristics
Ocular Features: 

Optic atrophy is a major ocular feature and the primary cause of visual impairment.  A minority (25%) of patients also have a diffuse fleck retinopathy with a bull’s eye maculopathy.  Later the retinopathy may resemble retinitis pigmentosa with a bone spicule pattern. Nystagmus is often present.  These signs usually follow systemic signs such as difficulties in locomotion.  An apraxia of eyelid opening has been noted and some patients have blepharospasm. 

Systemic Features: 

This is a progressive disorder of the basal ganglia with prominent symptoms of extrapyramidal dysfunction.  Onset is in early childhood or in the neonatal period with delayed development and sometimes mental retardation.  Choreoathetoid writhing movements, stuttering, dysphagia, muscle rigidity, and intermittent dystonia are prominent features.  Seizures are uncommon.  Older individuals may exhibit dementia and ambulation is eventually impaired.  The MRI usually shows an area of hyperintensity in the medial globus pallidus that has been called the ‘eye of the tiger’ sign but this is not pathognomonic.  Axonal degeneration with accumulation of spheroidal inclusions can be seen histologically. 

Genetics

The title of this disorder ‘neurodegeneration with brain iron accumulation’ actually refers to a group of disorders with somewhat common characteristics.  Pentothenate kinase-associated neurodegeneration or NB1A1 (234200) is  the most common of these. 

Types  NBIA2A (256600) and NBIA2B (610217) are caused by mutations in the PLA2G6 gene (22q13.1).  The former can be seen neonatally but usually has its onset in the first two years of life and is sometimes called infantile neuroaxonal dystrophy or Seitelberger disease.  Death may occur before the age of 10 years.  Signs of motor neuron and cerebellar disease are more prominent than in NB1A1. 

NBIA2B has a later onset (4-5 years) and profound sensorimotor impairment but there are many overlapping features and the nosology is confusing.  Mutations in the FTL gene cause yet another form designated NBIA3 (606159) but ocular signs seem to be absent. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is evidence that treatment with deferiprone reduces the amount of iron accumulation in the globus pallidus with motor improvement in at least some patients.  Most patients require supportive care.

References
Article Title: 

Spinocerebellar Ataxia 7

Clinical Characteristics
Ocular Features: 

Pigmentary changes in the retina are somewhat variable but often begin with a granular appearance in the macula and spread into the periphery.  The macula often becomes atrophic and dyschromatopsia is common.   Retinal thinning is evident, especially in the macula.  Decreased visual acuity and loss of color vision are early symptoms and the ERG shows abnormalities of both rod and cone function.  External ophthalmoplegia without ptosis is a frequent sign.  Most adults and some children eventually are blind. 

Systemic Features: 

Symptoms of developmental delay and failure to thrive may appear in the first year of life followed by loss of motor milestones.  Dysarthria and ataxia are nearly universal features while pyramidal and extrapyramidal signs are more variable.  This can be a rapidly progressive disease and children who develop symptoms by 14 months are often deceased before two years of age.  However, adults with mild disease can survive into the 5th and 6th decades.  Peripheral neuropathy with sensory loss and motor deficits are usually present to some degree but the range of clinical disease is wide.  Cognitive decline and some degree of dementia occur sometimes. 

Genetics

Spinocerebellar ataxia 7 is caused by expanded trinucleotide repeats (CAG) in the ATXN7 gene (3p21.1-p12) and inherited in an autosomal dominant pattern.  The number of repeats is variable and correlated with severity of disease.  Most patients with 36 or more repeats have significant disease. This disorder is sometimes classified as a progressive cone-rod dystrophy.  It is sometimes referred to as olivopontocerebellar atrophy type III or OPCA3.

This disorder exhibits genetic anticipation especially with paternal transmission as succeeding generations often have earlier onset with more severe and more rapidly progressive disease. This is explained by the fact that younger generations tend to have a larger number of repeats and sometimes the diagnosis is made in children before the disease appears in parents or grandparents.

Spinocerebellar ataxia 1 (164400) is a similar autosomal dominant disorder with many of the same clinical and genetic features.  It is caused by excess CAG repeats on the ATXN1 gene on chromosome 6. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known for the disease.  Low vision aids and mobility training may be useful in early stages. 

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: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 

Cerebral Amyloid Angiopathy

Clinical Characteristics
Ocular Features: 

Posterior polar cataracts appear during the third decade of life.

Systemic Features: 

Progressive hearing loss has its onset in the third decade and becomes severe in the 5th decade.  Progressive dementia, often in the form of paranoid psychosis, begins about age 50.  Cerebellar ataxia and intention tremor have their onset in midlife.  There is a diffuse atrophy throughout the brain and cranial nerves are demyelinated.  Blood vessels throughout the CNS, spinal cord and retina show an amyloid angiopathy.  Intracranial hemorrhage is a significant risk and, when lobar in location, carries a significant risk of mortality within months.  Death generally occurs in the 5th and 6th decades of life.

Genetics

Pedigree patterns in the few reported families are consistent with autosomal dominant inheritance.  A mutation has been found in the ITM2B gene located at 13q14.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Heredopathia ophthalmo-oto-encephalica

Stromgrem, E. Heredopathia ophthalmo-oto-encephalica. In: Myrianthopoulos, N.C. Handbook of Clinical Neurology. Neurogenetic directory. New York: Elsevier/North Holland (pub.) 42, Part I: 150-152, 1981.

Cerebrotendinous Xanthomatosis

Clinical Characteristics
Ocular Features: 

Juvenile cataracts are the primary ocular feature of this disorder and are found in virtually all patients.  These often cause the first symptoms and become evident in the first decade and almost always by the third decade of life.  Lens opacification may require extraction at that time and aspirated lens material may contain lipid-containing vacuoles.  However, some cataracts may not be diagnosed until the 5th or 6th decades after the onset of neurological symptoms, usually because the opacities are located in the peripheral cortex and do not cause visual symptoms. 

Optic atrophy occurs in nearly half of affected individuals.  Yellowish flakes resembling cholesterol crystals can sometimes be seen in the vitreous. The fundus may have scattered hard exudates and cholesterol-like deposits along the vascular arcades and arterioles show evidence of atherosclerosis.  RPE window defects are common.

Systemic Features: 

CTX has serious systemic neurologic signs and symptoms resulting from a deficiency of a mitochondrial enzyme, sterol 27-hydroxylase.  The result is reduced bile acid synthesis and increased levels of cholestanol in plasma, tissues, and CSF.  This results in a characteristic phenotype of tendon xanthomas, and neurological dysfunction including mental regression or illness, cerebellar ataxia, peripheral neuropathy, seizures, and pyramidal signs to various degrees.  Neonatal jaundice and diarrhea are common.

Genetics

This autosomal recessive disorder results from a mutation in the CYP27A1 gene (2q33-qter) encoding sterol 27-hydroxylase.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

This is a treatable disorder in which administration of chenodeoxycholic acid (CDCA) is beneficial.  This compound is virtually absent from bile in people with CTX.  Exogenous administration reduces high levels of cholesterol and cholestanol in the CSF, tissues, and plasma with improvement in mental function and signs of peripheral neuropathy and cerebellar dysfunction.  It is frequently given in combination with other HMG-CoA inhibitors such as pravastatin.  Early diagnosis and treatment are important.

References
Article Title: 

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