ATP13A2

Kufor-Rakeb Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have a supranuclear gaze paresis.  Patients later may have dystonic oculogyric spasms.

Systemic Features: 

This is a rapidly progressive neurodegenerative disorder with juvenile onset.  First signs of Parkinisonism are evident between the ages of 12 and 16 years of age.  Within a year of onset severe motor handicaps develop along with some degree of dementia with aggression and visual hallucinations.  Cognitive decline is often a feature.  Fine tremors in the chin may be seen along with other extrapyramidal signs but these are not prominent in the limbs.  Instead there is often rigidity and bradykinesia.  Dysphagia, dysarthria, and ataxia are features in many patients.  Peripheral sensory neuropathy and anosmia are present in some individuals. 

Brain imaging often reveals generalized atrophy of the cerebellum, cerebral cortex, and brainstem.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).  

Biallelic mutations in the same gene are also responsible for spastic paraplegia 78 (617225) with somewhat similar clinical features except for the general absence of Parkinsonism.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There may be an initial therapeutic response to L-DOPA but this is often not maintained

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Spastic Paraplegia 78

Clinical Characteristics
Ocular Features: 

Reduced upgaze with nystagmus and strabismus have been reported.  

Systemic Features: 

This progressive neurodegenerative disorder usually has its onset in young adults but the signs and symptoms are highly variable.  Ambulation and gait difficulties combined with spasticity and lower limb weakness are common signs.  Ataxia and dysarthria are also important signs.  Some individuals have dementia while others have only mild cognitive impairment.  Some individuals have mild signs of Parkinsonism.

Brain imaging may show cerebellar and cortical atrophy with a thin corpus callosum. 

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).

The same gene is also mutated in the Kufor-Rakeb syndrome (606693), an early-onset form of Parkinsonism.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016 Jul;139(Pt 7):1904-18.

PubMed ID: 
27217339

Neuronal Ceroid Lipofuscinoses

Clinical Characteristics
Ocular Features: 

At least 13 genotypically distinct forms of neuronal ceroid lipofuscinosis have been described.  The ocular features are highly similar in all forms with blindness the end result in all types (although not all cases with an adult onset suffer vision loss).  The onset of visual signs and symptoms is highly variable.  Optic atrophy is the most common finding which may occur as early as two years of age in the infantile form.  Night blindness is a symptom in those with a later onset but panretinal degeneration with unrecordable ERGs eventually occurs.  Pigmentary changes throughout the retina are often seen and sometimes occur in a bull’s-eye pattern.  Retinal blood vessels may be attenuated and lens opacities of various types are common. 

Systemic Features: 

The neuronal ceroid lipofuscinosis are a group of inherited neurodegenerative lysosomal-storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment causing damage predominantly in the central nervous system.  The result is a progressive encephalopathy with cognitive and motor decline, eventual blindness, and seizures with early death.  While early descriptions distinguished several types based primarily on age of onset, genotyping has now identified responsible mutations in at least 10 genes and time of onset is no longer considered a reliable indicator of the NCL type. 

Genetics

The NCLs are usually inherited in autosomal recessive patterns with the exception of some adult onset cases in which an autosomal dominant pattern is sometimes seen.

The various forms of NCL are often divided according to ages of onset but overlap is common.  Thus the congenital form (CLN10; 610127), caused by a mutation in the CTSD gene at 11p15.5, can have an onset of symptoms at or around birth but also is responsible for an adult form (Vida infra).  The CLN1 infantile form (256730), caused by a mutation in the PPT1 gene at 1p32, has an onset between 6 and 24 months  There are several mutations causing late infantile disease (CLN2, 204500) involving the TPP1 gene (11p15.5) leading to symptoms between 2-4 years, the CLN5 gene (256731) at 13q21.1-q32 with onset between 4 and 7 years, the CLN6 gene (601780) at 15q21-q23 showing symptoms between 18 months and 8 years, and the CLN8 gene (610003) at 8p23 with symptoms beginning between 3 and 7 years.  Another early juvenile form (CLN7; 610951) is caused by mutations in MFSD8 (4q228.1-q28.2).

A juvenile form (sometimes called Batten disease or Spielmeyer-Vogt with onset between 4 and 10 years results from mutations in CLN3 (204200) as well as in TPP1, PPT1, and CLN9 (609055).  An adult form known as ANCL or Kuf’s disease results from mutations in CTSD, PPT, CLN3, CLN5, and CLN4 (204300) and has its onset generally between the ages of 15 and 50 years. 

Homozygous mutations in the ATP13A2 gene (1p36.13), known to cause Kufor-Rakeb type parkinsonism (606693), have also been found in NCL.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.  However, there is recent progress in the application of enzyme-replacement therapies in the soluble lysosomal forms of CNL.  Gene therapies and the use of stem cells also hold promise. 

References
Article Title: 
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