Abstract
In the following case-study, Joshua is a newborn infant presented by his parents Samuel and Rachel to the pediatric outpatient unit of Robertsbridge, Sussex for screening and medical advice for sporadic vomiting at the time of breast feeding and seizure-like episodes. Samuel and Racheal also report sweet odor in the urine and loss of weight. Blood tests demonstrated increased concentrations of leucine and isoleucine. Genetic testing on the skin biopsies reveal mutation at Exon 6, c.659C>T of the of BCKDHA gene with a protein level p. A220V and Joshua exhibits about 1.5 % lesser than normal deficiency in the functioning of the branched-chain amino acid aminotransferase activity (BCAA). All these symptoms, clinical test results and genetic testing data are clearly indicative of Maple Urine Syndrome Disease (MUSD), which is an autosomal recessive disorder leading to defective metabolism of branched-chain amino acids. Deficiency in the enzyme complex leads to accumulation of amino acids and causes mental retardation and sweet odour of urine. Treatment and management strategies include dietary restriction of BCAA’s, surgical liver transplantation, and thiamine supplementation. Early diagnosis and prompt treatment of symptoms and therapy is important for overall survival and management of the disease. Genetic counselling and appropriate prenatal diagnosis including genetic testing of associated mutations is crucial for immediate management of the affected neonates and their survival.
Introduction
Joshua is apparently suffering from Maple Urine Syndrome Disease (MUSD), also termed as branched-chain ketoaciduria. This is an autosomal recessive genetic disorder that imparts a characteristic maple syrup like sweet odor to the urine of infants. In this condition, branch chain amino acids (BCAA) such as isoleucine, leucine and valine get accumulated causing neurodegeneration in infants . The urine is composed of ketoacids, which indicates a metabolic deficiency. Accumulation of isoleucine in particular is linked to the typical maple syrup odor.
Pathogenesis
The enzymatic deficiency may be attributed to mutations in the branched chain alpha-keto acid dehydrogenase (BCKD) complex to the stage of decarboxylation of the branched-chain amino acids. This enzyme, which is an inner mitochondrial enzyme complex involved in the catalysis of branch-chain amino acids leucine, valine and isoleucine. The catalytic components of the complex alpha-2-beta-2 branched chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). Genetic testing performed on Joshua’s samples uncovered a mutation on Exon 6, c.659C>T. Researchers have demonstrated mutations at the c.659C>T (p. A220V) location to be associated with MSUD .
Alternative forms of the disease
Currently there exist five known clinical forms of MSUD; thiamin-responsive, classic, intermediate, intermittent, and dihydrolipoamide dehydrogenase (E3)-defective, depending on the extent of the disease, reaction to thiamin therapy, and the defective gene locus.
The classic version of the disease first discovered by Menkes is the most intense with 0–2% of normal BCKDC activity and is characterized by early onset of ketoacidosis . In this case study, Joshua’s specimen represents about 1.5 % of the normal BCKDC activity. The living children often exhibit mental retardation. Symptoms usually present in newborns as old as 2-3 days old (breast-feeding may postpone the initiation of symptoms to the second week of life. The affected neonates exhibit vomiting, significant loss of weight, disturbed feeding and lethargy within 48 hours of delivery, as in case of Joshua . Neurological symptoms such as dystonia, encephalopathy and seizures may develop, which was also visible in Joshua . The characteristic maple syrup odor is prominent in cerumen right after birth and in urine by five to seven days after birth. Intermittent apnea, opisthotonus, and typical movements such as "fencing" and "bicycling" may be prominently observed by age four to five days after which coma and central respiratory failure may persist. Preventive diagnosis of newborn patients, prior to manifestation of neurological signs of MSUD, may considerably decrease lifetime potential of mental retardation and functional damage. Post neonatal phase, chronic leucine intoxication and neurologic exacerbation may develop at any age owing to the cumulative protein degradation caused due to physiological stress, injury and infections .
The intermediate and moderate forms are relatively subtler in clinical phenotype and are correlated to greater BCKDC activity. The typical characteristic of intermittent version of the disease is its late initiation and episodic form. These individuals demonstrate normal infantile growth and intellectual development. They are also resistant to a regular leucine intake and show normal plasma amino acid levels and only moderate increases in BCAAs.
The thiamin-responsive form of MSUD first shown by Scriver and colleagues reacted favorably to thiamin supplementation in diet. Mutation and impairment in the Dihydrolipoamide dehydrogenase (E3) component of BCKDC causes combinatorial ketoacid dehydrogenase deficiencies and is the most intense form among all the five MSUD phenotypes . These individuals are not sick in the neonatal period and may manifest the disease in the later stages of life. These patients are usually managed with a combination of BCAA restricted diet and thiamine supplementation.
Dietary therapy
This form of therapy involves limiting BCAA contents in the diet of affected patients. This may include se of hemodialysis/hemofiltration to eliminate BCAAs from the extracellular region. Use of commercial medical kits has also been rampant for MSUD individuals. Dietary management should permit age-relevant tolerance of leucine, isoleucine, and valine, and preserve steady plasma BCAA levels and BCAA concentration ratios. A “sick-day” formula method with the absence of leucine and supplemented with calories, isoleucine, valine, and BCAA-free amino acids in combination with rapid and recurrent amino acid monitoring permits for several catabolic diseases to be managed .
Liver transplantation
Orthotropic liver transplantation has been conducted on MSUD patients, which was proven to be effective in regulating plasma BCCA levels . For example, in a patient suffering from classis MSUD, the plasma leucine levels dropped dramatically to normal concentrations, post liver transplantation, despite of being on a normal diet. This was suggestive that the transplanted liver alone had the ability to degrade more than 90 % of BCCA .
Thiamine supplementation
One strategy to treat the category of patients with thiamine-responsive phenotype is supplementing with thiamine (vitamin B-1). Administration of patients with thiamine supplements of dose (10-1000 mg/d), has been a common therapy prescribed by pediatricians, owing to lack of side effects due to of vitamin B-1 and its excretion into the urine.
Genetic Counselling and Prenatal Diagnosis
Since MSUD manifested in Joshua, Samuel and Racheal are expected to be carriers. If they intend to conceive another child, they would be advised to undergo prenatal diagnosis on cultured amniocytes or chorion villus cells. Autosomal recessive diseases manifest only if an individual receives both copies of their mutant genes, on each from their carrier parents. Thus Samuel and Rachel have a 25 % chance of producing an affected child with MSUD and a 50 % risk of producing a carrier, and 25 % chance of producing an unaffected normal child . If Samuel and Racheal decide to go ahead with another child, they should be informed that Joshua’s newborn sibling could be screened for the mutation c.659C>T (p. A220V) by genetic testing of the umbilical cord at a molecular level. They could also perform a plasma amino acid analysis at 24 hours of life. Early phase detection would aid in prompt management and treatment of asymptomatic infants .
References
Acton, A. (2012). Inborn Metabolic Brain Diseases- Advances in Research and Application. Atlanta, Georgia: ScholarlyEditions.
Chuang, D. T. (2006). Lessons from Genetic Disorders of Branched-Chain Amino Acid Metabolism. American Society for Nutrition, 136, 2435-2495.
Maple Syrup Urine Disease. (n.d.). (online) available at http://patient.info/doctor/maple-syrup-urine-disease
Strauss, K. A. (2013). Gene Reviews. Maple Syrup Urine Disease. Seattle, WA.
