nystagmus

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 is a complex form of spastic paraplegia in which primarily lower limb spasticity is associated with dysarthria, sensory disturbances, cognitive deficits, muscle wasting and mild ataxia.  There is, however, considerable variability in age of onset and rate of symptom progression.  The first motor symptoms are often evident when children start walking, which is often delayed and clumsy.  However, evidence of spasticity may be present in children under 1 year of age.   Some patients have normal mental functions while others are considered mentally retarded.  The MRI reveals patchy leukodystrophy and degeneration of both corticospinal and spinocerebellar tracks was found in an autopsied individual.  Progression is relentless with many individuals requiring assistive devices such as crutches or walkers by early adult life.

Mannosidosis is a highly variable multisystem disorder.  Onset may be in infancy but in other patients symptoms appear later in the first decade.  Progression of disease is more rapid in individuals with early onset (type 3) with rapid mental, motor deterioration and early death.  The characteristic coarse facial features usually are evident later in milder cases (types 1 and 2) that have mild or moderate intellectual disabilities.  Regardless, mannosidosis is relentlessly progressive with mental deterioration and motor disabilities.  Ataxia is a common feature.  Dental anomalies (diastema), large ears, macroglossia, joint stiffness,, hepatosplenomegaly, enlarged head circumference, hearing loss (sensorineural), increased susceptibility to infections, dysarthria, and spondylolysis may be present.

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.

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones.  The amount of cognitive impairment is variable.  Congenital cardiac defects, ichthyosis, and hypertrichosis may be present.  The skin over the dorsum of the hands and feet often appears dark.  Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common.  Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

The hand and foot malformation is severe, described as split-hand/split foot deformity.  It may involve all four extremities or just the upper extremity with monodactyly.  When the hand is involved, it may be called a lobster-claw deformity, or ectrodactyly.  The middle digit is characteristicly missing but other fingers and toes are sometimes absent.

The teeth erupt late, some may be missing and others are often poorly formed. Frontal bossing, sunken cheeks, and thick and everted lips may be part of the facial phenotype.