spastic quadriplegia

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics
Ocular Features: 

Optic atrophy is sometimes present.  Nystagmus, and strabismus are seen in some patients.  A pigmentary retinopathy was found in one individual.

Systemic Features: 

This is a clinically heterogeneous disorder with extensive neurological deficits.  Patients have feeding and swallowing difficulties from the neonatal period.  There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities.  Some develop seizures and few achieve normal developmental milestones.  Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy.  However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis.  Ataxia eventually develops in most patients. 

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination. 

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues.  Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition.  The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID: 
28905505

Cerebral Palsy, Spastic Quadriplegic, 3

Clinical Characteristics
Ocular Features: 

One family with 4 affected sibs has been reported but without detailed information on ophthalmological findings.  Strabismus reported as exotropia in one individual, and "convergent retraction nystagmus" in another was present.  Supranuclear gaze palsy was described in one individual. 

Systemic Features: 

Borderline microcephaly has been reported.  Evidence for global neurologic disease, primarily spasticity, may be present as early as 3 months of age.  Intellectual disability ranges from borderline to severe.  Progression is somewhat variable but by the second decade there may be sufficient spastic quadriparesis and cognitive impairment that full time assistive care is required.  Dysarthria and dysphagia are also features and gastrostomy feeding tubes may be required to maintain nutrition.  Seizures are uncommon.

The MRI does not show major structural abnormalities and an EEG in one patient revealed only bifrontal spike-waves.

Genetics

This condition is caused by homozygous mutations in the ADD3 gene (10q24).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in gamma adducin are associated with inherited cerebral palsy

Kruer MC, Jepperson T, Dutta S, Steiner RD, Cottenie E, Sanford L, Merkens M, Russman BS, Blasco PA, Fan G, Pollock J, Green S, Woltjer RL, Mooney C, Kretzschmar D, Paisan-Ruiz C, Houlden H. Mutations in gamma adducin are associated with inherited cerebral palsy. Ann Neurol. 2013 Dec;74(6):805-14.

PubMed ID: 
23836506

Pelizeaus-Merzbacher Disease

Clinical Characteristics
Ocular Features: 

Nystagmus is the major ocular feature in this disease and may appear as early as the first weeks of life in severe cases.  However, more mildly affected individuals may never have nystagmus and, further, it can disappear later.  The ocular movements are usually pendular but may have horizontal and rotatory components as well.  The presence of nystagmus is diagnostically important as it is an uncommon finding in other leukodystrophies.

Systemic Features: 

The classic disease is infantile in onset with hypotonia, titubation, weakness, stridor, respiratory problems, and even seizures often noted in the first weeks of life.   Ataxia, spasticity and cognitive delay are soon apparent.  Infants affected early and severely may never achieve normal motor or mental milestones whereas those less severely affected may at some point ambulate and acquire some language skills.  However, acquired skills may be lost by adolescence.  Survival to the sixth decade of life is common but those with the most severe form of disease may not live beyond the second decade. 

This is an X-linked recessive disorder in which only males have the complete syndrome.  However, multiple carrier females have been studied and many have subtle evidence of disease mainly in gait and motor control.

Genetics

Pelizeaus-Merzbacher disease is the result of mutations in an X-linked gene PLP1 (Xq22).  It is inherited in an X-linked recessive pattern.  Duplication of the PLP1 gene is more common than point mutations.  The signs and symptoms are not diagnostic of PMD as mutations in other genes can cause a similar phenotype. 

Spastic paraplegia-2 (SPG2; 312920)is an allelic disorder in which nystagmus and optic atrophy are also found in some patients.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no effective treatment for this disease.  Airway protection and seizure control should be applied in specific situations.  Patients often need a feeding tube for adequate nutrition.

References
Article Title: 
Subscribe to RSS - spastic quadriplegia