ataxia

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

This mitochondrial DNA depletion syndrome allows normal development in the first year of life.  By 10-18 months of age, muscle weakness and coordination become evident.  Deep tendon reflexes are diminished or absent.  The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound.  Generalized seizures are common.  Facial and limb dyskinesia of an athetoid nature is evident to a variable degree.  A sensory polyneuropathy develops in many patients.  Cerebellar atrophy is evident on neuroimaging.

Neurosensory hearing loss may become evident late in the first decade of life.  The amount of hearing loss is progressive, leading eventually to profound deafness.  Some patients experience a complete loss of vestibular caloric responses. 

Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.

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.

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Children have severe psychomotor delays from birth and have severe mental retardation.  Speech and normal motor function never develop fully.  Thoracic kyphosis begins in late childhood and contractures develop in the elbows and knees.  A CAT scan in one patient revealed only normal findings.  Facial features have been described as ‘coarse’ with prominent lips, broad nasal bridge, and a bulbous nose.  Some individuals with this condition have lived into the 5^th decade.  Ataxia is usually present although the cerebellum may be normal on MRI.

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.