spastic tetraplegia

Encephalopathy, Progressive, with Amyotrophy and Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is present.

Systemic Features: 

This is a progressive neurodegenerative condition in which hypotonia and delayed development are evident between birth and 14 months of age.  Developmental milestones, if attained, soon regress accompanied by distal amyotrophy, cognitive impairment that may be severe, ataxia, spastic tetraplegia, dysarthria, and scoliosis.  Seizures often occur.

Brain imaging reveals cerebellar and cerebral atrophy.  Iron accumulation may be seen in the pallidum and substantia nigra.  The corpus callosum appears abnormally thin.  Muscle biopsy shows evidence of denervation atrophy.

Genetics

Homozygous or compound heterozygous mutations in the TBCE gene (1q42.3) can cause this disorder.  

Biallelic mutations in the same gene also cause Kenny-Caffey syndrome type 1 (244460) and a hypoparathyroidism dysmorphism syndrome (241410).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

PubMed ID: 
27666369

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 1

Clinical Characteristics
Ocular Features: 

Nystagmus, strabismus and sometimes optic atrophy have been noted.  Poor fixation may be present.   

Systemic Features: 

This progressive disorder can be evident at birth based on the facial dysmorphism.  The face is triangular, the forehead is prominent, the nose is small, the ears appear large and low-set.  The mouth appears wide with a thin upper lip.  Early development may be near normal for the first 6 months but thereafter psychomotor regression and slow physical growth are evident.  Patients have microcephaly and seldom achieve normal milestones.  Spasticity in the extremities and truncal hypotonia with distal muscle atrophy are evident.  The face appears triangular, the forehead is prominent, the nose is small, and the ears appear large and low-set.  Pectus carinatum and pes varus may be present.   Males often have cryptorchidism.

Brain imaging has revealed cerebellar atrophy and "while matter abnormalities".  Sural nerve biopsies show evidence of infantile neuroaxonal dystrophy.

Some individuals are less severely affected, retain the ability to speak, and are able to walk at least into the second decade of life.

Genetics

Based on transmission patterns this condition is inherited as an autosomal recessive disorder caused by mutations in in the NALCN gene (13q32.3-q33.1.

For somewhat similar disorders caused by mutations in other genes see IHPRF2 (616801) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 
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