TPP1

Spinocerebellar Ataxia, Autosomal Recessive 7

Clinical Characteristics
Ocular Features: 

Nystagmus and saccadic pursuit eye movements are common signs.  Some patients complain of diplopia.  No other ocular abnormalities are present.

Systemic Features: 

Symptoms have their onset in late childhood and are slowly progressive.  Walking and balancing are difficult.  Dysarthria, postural tremor, and limb ataxia are evident in adults.  Fine motor movements are difficult and there is often a tremor in the hands.  Deep tendon reflexes are abnormally brisk and extensor plantar responses are seen in some individuals.  Vibration sense may be diminished.  These signs are variable as is the rate of progression.  Usually patients remain mobile and productive through the fourth decade of life.  They may become wheelchair-bound by the fifth or sixth decade.  There is no cognitive impairment.

Genetics

This is an autosomal recessive condition secondary to homozygous mutations in TPP1(11p15).

The same gene is mutated in neuronal ceroid lipofuscinosis 2 (CLN2, 204500), a far more serious condition with epilepsy, optic atrophy, retinal degeneration, and a rapidly progressive course leading to early death in many individuals. It has been suggested that mutations resulting in the more severe CLN2 phenotype completely or nearly completely abolish TPP1 enzyme activity whereas those that cause SCAR7 simply result in diminished activity.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological symptoms but physical therapy and mobility devices could be helpful in maintaining ambulation.  Speech therapy could be useful for dysarthria.

References
Article Title: 

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, the Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

Sun Y, Almomani R, Breedveld GJ, Santen GW, Aten E, Lefeber DJ, Hoff JI, Brusse E, Verheijen FW, Verdijk RM, Kriek M, Oostra B, Breuning MH, Losekoot M, den Dunnen JT, van de Warrenburg BP, Maat-Kievit AJ. Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, the Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease). Hum Mutat. 2013 Feb 15. [Epub ahead of print].

PubMed ID: 
23418007

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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