Other important disorders

Other important disorders:

1. Inclusion-cell (I-cell) disease (mucolipidosis II /ML II): It is caused by a mutation in the GNPTAB gene and is inherited in an autosomal recessive manner. Deficiency in the enzyme UDP-N-acetylglucosamine-1-phosphotransferase causes I cell disease. This interferes with tagging of proteins bound for lysosomes with mannose- 6- phosphate which causes them to be secreted outside the cell. The lysosomes lack acid hydrolases because of that and they cannot break down complex macromolecules causing their accumulation. I-cell disease can manifest at birth with coarse features, corneal clouding, organomegaly, hypotonia, and gingival hyperplasia. Failure to thrive, Kyphoscoliosis, lumbar gibbus, and restricted joint movement are often present, and there may be hip dislocation, fractures, hernias, or bilateral talipes equinovarus, severe psychomotor retardation. Death occurs due to cardiorespiratory complications. I Cell Disease is diagnosed by testing the blood or urine for high levels of mucolipids, elevated plasma lysosomal enzyme concentration, decreased concentration of lysosomal enzymes in cultured fibroblasts, presence of inclusion bodies in peripheral blood lymphocytes and low levels of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity in white blood cells. Differential is from Hurlers Syndrome.
2. Hurler and Hunter syndromes: They are mucopolysaccharidosis (MPS), a type of lysosomal storage disorder characterized by the deposition of mucopolysaccharides and glycosaminoglycans in tissues.

Comparison between Hurler and Hunter syndromes

Hurler syndrome (MPS I)

• Most severe form
• Autosomal recessive
• Deficiency of the enzyme alpha-L-iduronidase
• Dermatan and heparan sulfates accumulate
• Presents in infancy with developmental delays, coarse facial features, hepatosplenomegaly, recurrent urinary and upper respiratory tract infections, noisy breathing, persistent nasal discharge, clouding of the cornea, large tongue, musculoskeletal deformities and mental retardation
• Corneal clouding present
• Less severe form is called Scheie syndrome

Hunter syndrome (MPS II)

• X linked recessive
• Deficiency of iduronate sulfatase
• Dermatan and heparan sulfate accumulates
• Presents in early childhood with delayed development, coarsening of facial features, macrocephaly, hepatosplenomegaly, delayed tooth eruption, hearing loss, mental retardation, large tongue
• Corneal clouding absent

3. Zellweger syndrome and Refsum disease: Proteins destined to reach the peroxisomes are tagged with C terminal peptides that function as a peroxisome targeting signal. In Zellweger syndrome and Refsum disease this process is improper. In Zellweger Syndrome, very long chain fatty acids accumulate in the peroxisomes and there is disruption of myelin synthesis causing hepatomegaly, mental retardation, seizures, hypotonia, retinal degeneration etc. Refsum disease is a less severe form with accumulation of phytanic acid, anosmia, vision loss, retinitis pigmentosa, scaly skin and arrhythmias.

4. Disorders of galactose metabolism

Galactokinase deficiency or type II

• Deficiency of galactokinase enzyme
• Increase in galactose and galactitol
• Presents with cataracts
• Less severe disease

Classic galactosemia or type I

• Deficiency of galactose-1-phosphate uridyltransferase
• Increase in galactose, galactose-1-phosphate and galactitol
• More common
• Severe disease with cataracts, cirrhosis, mental retardation, lethargy, feeding problems, sepsis especially E.coli , failure to thrive
• Premature ovarian insufficiency may occur

In both disorders, reducing substance (galactose) will be present in urine. If infants with classic galactosemia are not treated promptly with a low-galactose diet, life-threatening complications appear within a few days after birth. Breast milk, proprietary infant formulas containing lactose, cow’s milk, dairy products, and casein or whey-containing foods, medications with lactose and galactose are avoided. Women with classic galactosemia should maintain a lactose-restricted diet during pregnancy.

5. Disorders of fructose metabolism

Essential fructosuria

• Caused by a deficiency of fructokinase
• Fructosemia and fructosuria following ingestion of fructose and related sugars (sucrose, sorbitol)
• Benign condition, clinically asymptomatic
• Reducing substance present in urine*

Hereditary fructose intolerance

• Caused by a deficiency of fructose-1-phosphate aldolase or aldolase B
• Elevated levels of fructose and toxic fructose-1-phosphate
• Liver and kidney damage
• Presents with severe abdominal pain, vomiting, and hypoglycemia after fructose ingestion, aversion to sweets and fruits, prolonged vomiting, failure to thrive, jaundice, growth retardation, cirrhosis, GI bleeding
• Hypophosphatemia, decreased ATP, elevated AMP and uric acid
• Reducing substance present in urine*

*Common reducing substances that may be present in urine are glucose, fructose, lactose and galactose.

Therapy for fructose intolerance is a fructose-free diet. Early fructose restriction can prevent damage to the liver and kidneys.

6. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: It is a disorder of medium chain fatty acid β-oxidation. It presents in infancy with hypoketotic hypoglycemia, vomiting, lethargy, hepatomegaly, seizures, and coma triggered by illness or fasting. Management is by frequent feedings to prevent hypoglycemia, avoidance of fasting and restricting medium chain triglycerides such as coconut oil, MCT oil and some infant formulas.
7. Lesch-Nyhan syndrome: It is an X-linked recessive disorder caused by the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). It is a hereditary disorder of purine metabolism associated with increased uric acid production. It presents with compulsive self-mutilation (including biting and head banging), gout, kidney stones, bladder stones and moderate cognitive disability and involuntary muscle movements. Patients typically cannot walk, require assistance sitting, and generally use a wheelchair. Death occurs in early adulthood from renal failure.