hyperreflexia

This is a progressive disorder of neurological deterioration.  Age of onset (mean 16.4 years) and rate of neurological dysfunction are highly variable.  Gait difficulties are the most common presenting signs.  Some gait ataxia is usually present.  The lower limbs are more severely affected by spasticity and weakness and walking is often delayed with difficulty running and clumsiness in childhood.  Some patients (38%) are wheelchair-bound after disease duration of more than 33 years.  Dysphagia and dysarthria are uncommon. 

Some sensory impairments such as impaired vibratory sense, decreased proprioception, and absent touch sensation in the lower extremities are frequently present.  Urge incontinence of bladder and rectum is sometimes a feature.

Epilepsy and development delay are hallmarks of this condition.  The seizures are of multiple types and have their onset in the first year of life.  The EEG often shows diffuse slowing, multifocal spikes and hypsarrhythmia.  These are often difficult to control.  Severe intellectual disability is usually present.  Feeding difficulties are evident early and slow growth is common.  Hypotonia is common but hyperreflexia and spasticity are also reported.

Brain MRIs show delayed or reduced myelination.  Acquired microcephaly is often 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.

First signs and symptoms occur sometime in the first 5 years of life and often in the first year.   In 6 of 7 reported patients the presenting sign was nystagmus but one individual with reported onset of disease at age 5 years presented with ataxia.  Cerebellar signs, both truncal and limb, are usually present and the majority of individuals have evidence of dystonia.  Likewise, pyramidal signs are nearly always present.  Cerebellar dysarthria and titubation are often present with dystonic posturing and torticollis. 

Brain MRIs usually reveal cerebellar atrophy and widespread hypomyelination.  Two individuals in a single family had severe global psychomotor delays as well.  No sensory deficits were reported.  This disorder is progressive and patients in adulthood may require the use of a wheelchair.

Prominent foreheads are present at birth along with full cheeks and a prominent forehead.  Children grow rapidly in the first year eventually reaching the 90th percentiles in weight, height, and head circumference although neurologically they are developmentally delayed.  Speech and walking may be delayed as well.  While limbs have increased tone together with hyperreflexia, the trunk exhibits hypotonia.

Brain imaging reveals delayed myelination, dilated lateral ventricles, reduced while matter, and cerebral atrophy.

Onset of unsteadiness, gait ataxia, and cognitive decline are evident in the first or second decades of life.  Dysdiadokinesis, dysarthria, dysmetria, dystonia, athetotic movements, signs of Parkinsonism with tremor may also be present.  Some patients have a mild hearing loss.  Tissue from muscle biopsies are normal.  Brain imaging reveals cerebellar atrophy in some families and iron deposition in the basal ganglia in others.

Many patients are wheelchair-bound eventually.

Microcephaly becomes evident in the first year of life and seizures can appear in this period as well.  General developmental delays are present.  There may be evidence of Leigh-like basal ganglia disease.  Dysphagia may require the placement of a gastroscopy tube.  Truncal hypotonia can be so severe that sitting and head control are not possible.  However, there is often spasticity and hyperreflexia in the limbs.  EEG recordings show hypsarrhythmia.

Brain MRI may show increased T2 signaling in the global pallidus, thalamus, and the subthalamic nucleus.

Patients may never be able to sit or walk and usually do not develop speech.  

Head circumference is normal at birth but later in childhood falls behind in growth.  Neurodevelopment seems to plateau without regression.  Feeding difficulties may be present from birth and may require gastroscopy tube placement.  Motor skills are delayed and expressive language may never develop.  General irritability and increased muscle tone with hyperreflexia are usually present eventually resulting in joint contractures. 

EEGs , electromyography, and nerve conduction studies have been normal in 3 patients.  A brain MRI in one patient showed a leukodystrophic pattern in periventricular areas.  Variable cardiac malfunctions such as heart failure, LVH, and pericarditis were observed in several patients.

Sudden death following a short febrile illness has been reported to occur in three of the six affected children before the age of 15 years.