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Maple Syrup Urine Disease

Branched-Chain Ketoaciduria


Presentation

The classic MSUD would present the earliest among neonates from first to second week of life. They may present with lethargy, vomiting, irritability, abnormal movements, poor feeding habits and poor weight gain which are eminently the offshoot of the neurological effects of leucine accumulation in the brain and nerves [6].

The urine may give out its characteristic dark color as isoleucine is passed out unscathed by the enzymes that metabolizes it. The isoleucine build up may present in infants as a sweet smelling perspiration and urine. The metabolic crisis in older children may be exemplified by failure to feed and psychological stresses to the child, consequently due to the leucine, valine and isoleucine accretion from exogenous and dietary sources.

Comatose patients are portrayed by severe MSUD cases with brain edema and irreversible neurologic impairments due to ketotic hypoglycemia and the amino acid accumulation and in the neurons which may culminate into death.

Developmental Delay
  • Dietary compliance is necessary to prevent developmental delay and neurological symptoms.[patient.info]
  • MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits.[ncbi.nlm.nih.gov]
  • Untreated MSUD in infants may result to poor feeding, vomiting, lethargy and psycho-motor developmental delays while chronic complicated forms of MSUD may lead to seizure, coma and death.[symptoma.com]
  • Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood.[orpha.net]
Fatigue
  • […] ma·ple syr·up urine disease \ ˈmā-pəl-ˈsər-əp-, -ˈsir-əp- \ : an inherited disorder of amino acid metabolism that is characterized initially by an odor of maple syrup in the urine and in earwax and by vomiting, fatigue, irritability, and hypertonicity[merriam-webster.com]
  • Other common symptoms of MSUD include: Poor appetite Fatigue Seizures Vomiting Treatment for Maple Syrup Urine Disease When MSUD is detected during a newborn’s screening, treatment must start right away.[share.upmc.com]
  • In patients diagnosed with MSUD and on active therapy, a metabolic crisis of lethargy, fatigue, and seizure may occur during surges of amino acid accumulation from internal and exogenous sources.[symptoma.com]
  • Other early symptoms of the disease include vomiting, fatigue and lethargy, seizures, and poor feeding. The seizures in particular can be dangerous, sometimes leading to death or neurological damage.[disabilitybenefitscenter.org]
  • A metabolic crisis usually is indicated by: extreme fatigue or lethargy loss of alertness irritability vomiting When MSUD is undiagnosed, or metabolic crises are untreated, the following severe complications can occur: seizures swelling of the brain lack[healthline.com]
Feeding Difficulties
  • Symptoms of this disorder include: Coma Feeding difficulties Lethargy Seizures Urine that smells like maple syrup Vomiting When the condition is diagnosed, and during episodes, treatment involves eating a protein-free diet.[nlm.nih.gov]
  • The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements[dovepress.com]
  • Clinical Characteristics General description (for patients): Newborns are listless, have feeding difficulties, seizures, periods of interrupted breathing, global developmental delay, and growth deficiency. The urine has a maple syrup odor.[wohproject.org]
  • Symptoms Symptoms of this disorder include: Coma Feeding difficulties Lethargy Seizures Urine that smells like maple syrup Vomiting Exams and Tests These tests may be done to check for this disorder: Plasma amino acid test Urine organic acid test Genetic[ufhealth.org]
Death in Infancy
  • If left untreated, MSUD results in severe brain damage, coma, and death in infancy. MSUD can be effectively managed with dietary restriction of proteins. Approximately 1 in 125 Ashkenazi Jews is a carrier of Maple syrup urine disease.[knowyourgenes.org]
  • Early diagnosis of MSUD is essential to prevent neurological damage and death in infancy. Some states, but not all, have mandatory screening programs for MSUD.[diet.com]
Noncompliance
  • Metabolic decompensations (plasma leucine 380 μmol/L) were more frequent during the first year of life and after 15 years, mainly due to infection and dietary noncompliance, respectively.[ncbi.nlm.nih.gov]
Failure to Thrive
  • The major clinical features presented by MSUD patients include ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay, and mental retardation; however, the pathophysiology of this disease is poorly understood.[ncbi.nlm.nih.gov]
  • Repeated episodes result in progressive brain atrophy and intellectual disability. in some patients the initial presentation is quite unspecific including hypotonia, failure to thrive and developmental delay.[treatable-id.org]
  • If untreated, it progresses to irreversible mental retardation, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death.[mayomedicallaboratories.com]
  • Clinical considerations: Failure to thrive Feeding intolerance Vomiting Lethargy Tachypnea Ketoacidosis Maple syrup odor to urine Referral: If the infant has any signs or symptoms you may wish to consult with a pediatric metabolic specialist or you may[archildrens.org]
Osteopenia
  • After supplementation of zinc products and pamidronate, skin lesions and osteopenia improved gradually. Direct sequencing of the DBT gene showed a compound heterozygous mutation [4.7 kb deletion and c.650-651insT (L217F or L217fsX223)].[ncbi.nlm.nih.gov]
Retinal Damage
  • Glutamate has been reported to play an important role in retinal damage. Elevated glutamate levels have been reported in vitreous specimens from patients subjected to vitrectomy or buckling surgery for RRD.[ncbi.nlm.nih.gov]
Phenylketonuria
  • METHODS: A total of 370 dried blood spots (DBS) from healthy neonates, 44 DBS specimens from phenylketonuria neonates, and 38 DBS samples from 10 MSUD patients were retrospectively tested using the LC-MS/MS method.[ncbi.nlm.nih.gov]
  • Phenylketonuria (PKU): Deficiency of the enzyme PAH results in high levels of phenylalanine in the blood. Mental retardation results if the condition is not recognized.[webmd.com]
  • In some metabolic conditions such as phenylketonuria there appears to be an association between metabolic state of the patient and changes in the VEP. 9 10 The case we present had an absent VEP 4 days after admission but showed remarkable clinical and[bjo.bmj.com]
  • Babies currently have a heel prick blood test at 5 to 8 days old to test for 5 conditions where early detection and treatment will improve the long-term outcome for the child: phenylketonuria ( PKU ), congenital hypothyroidism ( CHT ), sickle cell disease[gov.uk]
Seizure
  • Clinical features were characterized by mental retardation, seizures, autistic features, and movement disorder in the form of dystonia.[ncbi.nlm.nih.gov]
  • Metabolite accumulation in the brain may cause chronic seizures, brain edema, coma and death.[symptoma.com]
Hyperactivity
  • They had good evolution: all remain asymptomatic, but 2 patients have attention deficit and hyperactivity disorder. Six patients with late diagnosis of classic MSUD were followed during 41 months.[ncbi.nlm.nih.gov]
  • Later, catabolic stress, infection or injury may cause acute, potentially fatal, leucine intoxication with vomiting, altered consciousness, ataxia and acute dystonia in toddlers and hallucinations, hyperactivity, focal dystonia, ataxia and choreoathetosis[orpha.net]
  • If untreated, it progresses to irreversible mental retardation, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death.[mayomedicallaboratories.com]
  • Children may suffer from attention disorders, impulsivity, or hyperactivity, while adults often develop mental illness. Nutrition therapy for MSUD Restriction of BCAAs is required.[consultant360.com]
  • Adolescents and adults with MSUD are at increased risk for attention deficit hyperactivity disorder (ADHD), depression and anxiety disorders. [ 2 ] Non-central nervous system involvement in MSUD can include: [ 2 ] Nutritional deficiencies: Chronic deficiency[patient.info]
Hyperreflexia
  • Cerebral edema: If neurological signs develop or worsen (vomiting, lethargy, hyperreflexia, clonus), suspect cerebral edema.[newenglandconsortium.org]
  • Watch for signs of increased intracranial pressure including the following: Papilledema Disorientation, combativeness Depressed level of consciousness Refractory vomiting Extremity hyperreflexia Bradycardic hypertension Watch for signs of impending brain[ncbi.nlm.nih.gov]
Peripheral Neuropathy
  • Peripheral neuropathy, although not identified previously as a clinical feature of MSUD, may become more common as chronic dietary restrictions and improved management of the disease allow survival into adulthood.[ncbi.nlm.nih.gov]

Workup

In prenatal phase, genetic studies derived from amniotic fluid and chorionic villus may already demonstrate an accumulation of the branched-chain amino acids which heralds the diagnosis of MSUD [7]. At birth, routine newborn screening detects may demonstrate an increased Fisher ratio of leucine and isoleucine which is suggestive of the disease.

Confirmatory tests for the newborn screening may be opted beyond the sixth day of life by elucidating the increases concentration of alloisoleucine in the plasma as marker of a non-carboxylated isoleucine metabolite [8]. Urine tests make use of a combination of gas chromatography and mass spectrometry to identify organic acids like pyruvate, lactate and ketoglutarate which are known end metabolites of leucine and isoleucine catalysis.

Valine Increased

Treatment

Dietary support remains a cornerstone in the management of MSUD. Patients with this genetic disorder may be given protein free diet to avert the unwanted deposition of leucine, isoleucine and valine in the plasma. Parenteral nutrition may be administered protein-free with sugar and fats to support growth and energy requirements.

Metabolic decompensation in infants may require aggressive glucose infusion up to 5-8 mg/kg/min to promote anabolism of proteins. In severe metabolic crisis, peritoneal dialysis may be a recourse to eliminate the toxic metabolites in the system. Infants may benefit from man-made milk formula devoid of the three amino acids. Liver transplants to infant patients have shown promising results in MSUD treatment [9].

Patients with the successful liver transplant have averted complication of brain retardation but will not permanently disrupt all metabolic decompensation in MSUD [10]. Patients in remission must follow a strict dietary regimen with close monitoring of the amino acid levels in the blood stream.

Prognosis

MSUD is a metabolic disorder with life threatening consequences if no medical attention is offered to the child. Even with adequate treatment, accumulation of the same amino acids as a result of high dietary consumption, acquired illnesses and severe stress may mimic the same metabolic consequences as that of a fulminant MSUD case. Strict dietary control and amino acid assay monitoring may be imperative for these patients [5].

It is medically possible for an MSUD infant to grow into a normal adult with adequate dietary counselling and medical therapy.

Complications

The unabated accumulation of leucine in the plasma can be attributed to the neurologic complications of delayed psycho-motor development and mental retardation in children. Metabolite accumulation in the brain may cause chronic seizures, brain edema, coma and death. In patients diagnosed with MSUD and on active therapy, a metabolic crisis of lethargy, fatigue, and seizure may occur during surges of amino acid accumulation from internal and exogenous sources.

Etiology

Maple Syrup Urine Disease is inherited via a recessive gene from both parents. This consequently means that both parents are neither suffering from the disease but are genetically carriers of the trait. The more common forms of MSUD are the classic form which is eminent at birth and those that are latent which manifest clinically late in childhood but can still assert the same medical complications and developmental delays if left untreated.

Epidemiology

In has been recorded, that 1 out of 180,000 birth in the United States has MSUD [2]. However, there are increased cases among inbred populations like the Mennonites in Pennsylvania where the ratio is 1 case per 176 births. MSUD has a greater penetrance in a genetic population with close consanguinity. It is also noted that Maple Syrup Urine Disease has been seen in all ethnicity worldwide.

Sex distribution
Age distribution

Pathophysiology

In the absence of the branched-chain α-ketoacid dehydrogenase that catalyzes the decarboxylation of the ketoacids of leucine, isoleucine and valine, this three amino acids remain free in the blood stream instead of being converted to the helpful energy compounds like acetyl CoA, Succinyl CoA and acetoacetate.

The excessive accumulation of Leucine in the plasma causes the neurologic defects observable in patients because it is readily transported through the blood brain barrier where it is metabolized to glutamine. The characteristic odor in MSUD is caused by the accumulation of the amino acid isoleucine in the plasma. The branched-chain α-ketoacid dehydrogenase complex found in the inner mitochondrial membrane has 3 variations of mutations (E1, E2, and E3 respectively). Genotypic to phenotypic expressions remains insignificant save for the E2 variants which are responsive to thiamine supplementation [3].

The E3 variant however, has an associated additional deficiency in pyruvate and α-ketoglutarate dehydrogenase [4].

Prevention

Maple Syrup Urine Disease can only be prevented with proper genetic counselling to parents with off-springs suffering from the disease. This also covers those in the population and family gene pool which may carry the recessive trait in their genes. Genetic study of the prenatal amniotic fluid may be in place for these cases.

Children born with high suspicion of MSUD should undergo confirmatory tests to prevent future problems.

Summary

Maple Syrup Urine Disease or MSUD is a hereditary genetic defect in the breakdown of leucine, isoleucine and valine amino acids due to the absence of the catabolic enzyme branched-chain α-ketoacid dehydrogenase. This disease is coined maple syrup because of the characteristic odor and dark color appearance of the urine of afflicted infants resembling that of burnt sugar or maple syrup [1].

This genetic defect appears benign at birth but may prove to be seriously complicated if left unchecked. Because of this, Maple Syrup Urine Disease is actively being included in the routine newborn screening in all infants for early detection and intervention. Untreated MSUD in infants may result to poor feeding, vomiting, lethargy and psycho-motor developmental delays while chronic complicated forms of MSUD may lead to seizure, coma and death.

Patient Information

People must embrace the idea that the complications of MSUD as a genetic disease may be averted effectively if one submits the infant for a complete newborn screening work-up. Mental retardation worldwide has been significantly lowered due to this innovation in neonatal pediatrics. Marriage counselling must include genetic diseases in the family to prevent the expression of this recessive trait.

References

Article

  1. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. Nov 1954;14(5):462-7.
  2. Snyderman SE, Norton PM, Roitman E, Holt LE Jr. Maple syrup urine disease, with particular reference to dietotherapy. Pediatrics. Oct 1964;34:454-72.
  3. Scriver CR, Mackenzie S, Clow CL, Delvin E. Thiamine-responsive maple-syrup-urine disease. Lancet. Feb 13 1971;1(7694):310-2
  4. Park HD, Lee DH, Hong YH, Kang DH, Lee YK, Song J, et al. Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. Ann Clin Lab Sci. Spring 2011;41(2):167-73.
  5. Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, et al. Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience. J Pediatr. Aug 10 2011
  6. Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid requirements and toxicity: the example of leucine.J Nutr. Jun 2005;135(6 Suppl):1531S-8S.
  7. Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr. Mar 1998;132(3 Pt 2):S17-23Mitsubuchi H, Owada M, Endo F. Markers associated with inborn errors of metabolism of branched-chain amino acids and their relevance to upper levels of intake in healthy people: an implication from clinical and molecular investigations on maple syrup urine disease. J Nutr. Jun 2005;135(6 Suppl):1565S-70S
  8. Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease.Eur J Pediatr. Dec 1999;158 Suppl 2:S60-4
  9. Mazariegos GV, Morton DH, Sindhi R, et al. Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United network for organ sharing experience. J Pediatr. Jan 2012;160(1):116-121.e1.

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Last updated: 2019-07-11 20:29