strabismus

There is great variability in the clinical signs among patients.  Most have developmental delays and intellectual disabilities combined with behavioral challenges such as anxiety, obsessive-compulsive disorders and features of autism spectrum disorders.  

Infants and young children may have feeding difficulties but may later develop constipation or diarrhea.  

Skeletal anomalies such as short stature, high palate, craniosynostosis, scoliosis, pes planus, hand contractures, and joint hypermobility have been reported.  The voice may be hoarse.

There is general psychomotor delay in development.  Intellectual disability (with IQs in the 50s) and hypotonia are common.  Speech is poor and sometimes absent.   Behavioral anomalies such as aggression and features of autism have been reported.  The anterior hairline is low, the mouth is wide with downturned corners, the nose is bulbous, the ears are large and low-set, and the teeth are often widely-spaced.  Cryptorchidism is common among males.

Renal and cardiac defects are common.  Brain MRIs often show cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes.

Symptoms may begin in early infancy or childhood.  Several neonates with irritability, hypertonia, increased startle reflexes, and stiffness have been reported.  Hypotonia may occur in the neonatal period though.  Intellectual disability and severe developmental delay are common and some patients are unable to follow simple commands.  Seizures of variable severity frequently occur at some point.  Speech may be absent.  Some patients are unable to walk while those that do have a clumsy, spastic gait.  Joint contractures may develop.

The most obvious dysmorphic feature are large ears.  Choreiform and stereotypic hand movements are sometimes present.  Feeding difficulties and sleeping problems may be noted.  Cortical atrophy and thinning of the corpus callosum has been seen on brain imaging.  One mildly affected individual was short in stature.

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.

This is a severe congenital neurodevelopmental disorder with global delay, hypotonia, and characteristic facies.  It is usually present at birth and soon manifest as a profound intellectual delay.  Most patients do not develop speech or independent motor skills.  Feeding difficulties are evident early and often require gastric tube placement for nutrition.  Failure to thrive is common.   Most patients have seizures of a tonic-clonic or atonic type which may be controlled with medication. 

Microcephaly, brachycephaly, plagiocephaly, and brachycephaly have been described.  A high forehead with frontal bossing, facial hypotonia, triangular facies have been described.  The ears are low-set and posteriorly rotated.  The upper lip is often thin and the mouth is commonly open.  The neck appears short, the nose is bulbous while the nasal bridge is prominent and the nares may be anteverted.

Brain imaging is normal in some patients but there is evidence of generalized cerebral atrophy, with a thin corpus callosum and decreased myelination in others.  Variable features such as scoliosis, hip contractures, muscle wasting, and dyskinesias are sometimes seen.

Six patients from 4 unrelated families of mixed ethnic backgrounds have been reported.  Infants within the first 4 to 6 months of life had evidence of developmental delay and neurodevelopmental regression.  Poor feeding and breathing difficulties are often noted in this period.  Other later signs are axial hypotonia, abnormal movements such as tremor, spasticity, hyperkinetic movements, dystonia with eventual regression of milestones.  Joint contractures and kyphoscoliosis may develop. 

Microcephaly was noted in several infants and brain imaging in all patients reveals abnormal T2- weighted signals in the brainstem and specifically in the basal ganglia.  Decreased activity in muscle mitochondrial respiratory complexes I, III, and IV has been documented.  Lactate may be increased in serum and the CSF.  Postmortem studies show brain vascular proliferation and gliosis in basal structures.