I cell disease

I cell disease in short

• A rare and severe subtype of mucolipidosis, this condition is marked by significant growth retardation, pronounced skeletal abnormalities (including dysostosis multiplex, craniosynostosis, joint contractures, and osteopenia), distinctive facial features, stiffened skin, obstructive airway issues, cardiomegaly, and profound global developmental delay.

Synonyms

• Mucolipidosis type II
• Mucolipidosis type II alpha/beta
• N-acetylglucosamine 1-phosphotransferase deficiency

Prevalence: <1 / 1 000 000

Inheritance: Autosomal recessive

Age of onset: Antenatal, Neonatal

How common is I cell disease?

• Mucolipidosis type II (MLII) and type III (MLIII) represent a spectrum of clinical severity, and available data—mostly over a decade old—is either reported separately or in combination.
• The combined global birth prevalence is estimated to range from 1 in 37,000 to 1 in 455,000. Specifically for MLII, birth prevalence in Europe has been reported between 1 in 123,000 and 1 in 2,000,000.
• A notable founder effect has been identified in the Saguenay–Lac-Saint-Jean region of Quebec, where the estimated birth prevalence is as high as 1 in 6,000.

What causes I cell disease?

• Mucolipidosis type II (MLII) is caused by mutations in the GNPTAB gene (located at 12q23.3), which encodes the alpha and beta subunits of the N-acetylglucosamine-1-phosphotransferase enzyme complex.
• These mutations disrupt the synthesis of mannose-6-phosphate (M6P), a critical marker on the glycan side chains of lysosomal enzymes that directs them to the lysosomes.
• In the absence of this M6P signal, the enzymes are incorrectly routed and secreted outside the cell instead of being delivered to lysosomes, resulting in their accumulation in tissues and the clinical manifestations of the disease.

What are the symptoms of I cell disease?

Very frequent symptoms

• Abnormal atrioventricular valve physiology
• Abnormal cardiovascular system morphology
• Coarse facial features
• Expressive language delay
• Gingival overgrowth 
• Hoarse voice
• Motor delay
• Postnatal growth retardation
• Protuberant abdomen 
• Restricted chest movement
• Short stature
• Thickened skin
• Umbilical hernia

Frequent symptoms

• Abnormal mitral valve morphology
• Abnormality of the thoracic cavity
• Cognitive impairment 
• Conductive hearing impairment
• Craniosynostosis
• Depressed nasal bridge
• Flat face
• Inability to walk
• Limitation of joint mobility
• Mitral regurgitation
• Narrow chest
• Obstructive sleep apnea
• Otitis media 
• Poor speech
• Pulmonary insufficiency
• Restrictive ventilatory defect

Occasional symptoms

• Abnormal aortic valve morphology
• Abnormality of long bone morphology
• Aortic regurgitation
• Appendicular hypotonia
• Axial hypotonia
• Cardiomyopathy
• Decreased movement range in interphalangeal joints
• Diastasis recti
• Dry hair
• Epicanthus
• Fine hair
• Hepatosplenomegaly
• Hip contracture
• Hip dislocation
• Inguinal hernia
• Knee flexion contracture
• Kyphosis
• Left ventricular hypertrophy
• Limited shoulder movement
• Limited wrist movement
• Oligohydramnios
• Patent foramen ovale
• Prominent metopic ridge
• Recurrent respiratory infections
• Shallow orbits
• Stridor
• Talipes equinovarus
• Telangiectases of the cheeks
• Weight loss
• White hair

Rare symptoms

• Gastrostomy tube feeding in infancy
• Respiratory failure requiring assisted ventilation
• Sensorineural hearing impairment
• Splenomegaly

Clinical description

• I cell disease patients present prenatally (hydrops fetalis), directly after birth or within the first months of live with dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, transient neonatal hyperparathyroidism inducing rickets-like bone disease (not always present), clubfeet, hypotonia and global developmental delay; all symptoms gradually worsen over time.
• Facial dysmorphism includes a flat face, shallow orbits with proptotic eyes (due to craniosynostosis), depressed nasal bridge, prominent mouth and gingival hypertrophy.
• Coarsening of facial features is progressive. Spinal cord compression develops over time. Postnatal growth (both length and weight) usually stops in the second year of life and contractures develop in all joints. Most patients never walk.
• Cardiac involvement most commonly includes the thickening and insufficiency of the mitral or aortic valves.
• Breathing is noisy due to the progressive narrowing of airways, mucosal thickening and stiffening of all connective tissues which, along with cardiac involvement, leads to cardiorespiratory insufficiency.

How is this condition diagnosed?

• Diagnosis is established through clinical and radiographic evaluation along with biochemical and molecular testing.
• Radiographs typically show progressive osteopenia and features of dysostosis multiplex, including widened and shortened tubular bones, hook-shaped deformities of the first and/or second lumbar vertebrae, and elongated pubic and ischial bones.
• Plasma and other body fluids exhibit markedly elevated levels of lysosomal hydrolases—5 to 20 times above normal—due to improper enzyme trafficking.
• Confirmation is achieved by identifying pathogenic mutations in the GNPTAB gene through molecular genetic testing.

Differential diagnosis

Differential diagnoses of I cell disease include

• Hurler syndrome
• the infantile form of galactosialidosis
• sialidosis type 2
• infantile form of free sialic acid storage disease
• hypocalcemic rickets
• Pacman dysplasia is in many instances the prenatal expression of I cell disease

Antenatal diagnosis

Antenatal diagnosis of I cell disease is possible in chorionic villi by molecular testing.

Genetic counseling

• The condition is inherited in an autosomal recessive manner.
• Genetic counseling is recommended for at-risk couples—those in which both partners are carriers of a disease-causing mutation.
• They should be informed that with each pregnancy, there is a 25% chance of having an affected child.

Management and treatment – How is I cell disease treated?

• There is currently no cure for MLII, and management is primarily supportive. Interventions such as cognitive stimulation programs, low-impact physical therapies (e.g., aqua therapy), occupational therapy, and speech therapy can provide developmental benefits.
• Care should be taken to prevent overfeeding. In cases of severe oral pain or infection, gingivectomy may be considered. Some patients may require respiratory support or assisted ventilation.
• Regular follow-up is essential—every three months during infancy and toddlerhood to monitor cardiac and respiratory function, and annually throughout early childhood.

What is the Prognosis of this condition?

• The prognosis is poor with a fatal outcome (most commonly due to cardiorespiratory insufficiency) most often occurring in early childhood.