Background Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic error, characterized by Branched Chain α-Keto-acid Dehydrogenase Complex (BCKDC) deficiency. Mutations in 3 genes can lead to abnormal metabolism and accumulation of leucine, isoleucine, valine and corresponding keto-acids. MSUD affects 1 in 185,000 infants globally. Seizure is a common presentation among neonates. However, in intermediate MSUD, seizures have a delayed and insidious onset, along with developmental     Case Report  We report a case of grand mal seizures in a patient with intermediate MSUD, presenting with multiple episodes of seizure, dystonia, spastic quadriplegia, involuntary micturition and oculogyric crisis.Seizures were managed successfully with intravenous lorazepam and other supportive measures. The patient was advised to strictly adhere to branched chain amino acid restricted diet.  Conclusion This case report emphasizes on the importance of medication adherence and dietary restrictions to prevent permanent psychomotor damage or death

Balraj Guhan

Gautam Satheesh

Niyas Ahammed

Suja Johnson

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Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                            7999 
Case Report (Pages: 7999-8002) 
 
http:// ijp.mums.ac.ir 
 
Maple Syrup Urine Disease Induced Grand Mal Seizures: A Case 
Report 
*Gautam Satheesh
1
, Suja Johnson
1
, Balraj Guhan
2
, Niyas Ahammed
21
 
 
 
1
Department
 
of Pharmacy Practice, National College of Pharmacy, Calicut, Kerala, India.  
2
Department of Paediatrics, KMCT Woman and Child Hospital, Calicut, Kerala, India. 
 
 
 
Abstract 
Background 
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic error, characterized by 
Branched Chain α-Keto-acid Dehydrogenase Complex (BCKDC) deficiency. Mutations in 3 genes 
can lead to abnormal metabolism and accumulation of leucine, isoleucine, valine and corresponding 
keto-acids. MSUD affects 1 in 185,000 infants globally. Seizure is a common presentation among 
neonates. However, in intermediate MSUD, seizures have a delayed and insidious onset, along with 
developmental     
Case Report  
We report a case of grand mal seizures in a patient with intermediate MSUD, presenting with multiple 
episodes of seizure, dystonia, spastic quadriplegia, involuntary micturition and oculogyric crisis. 
Seizures were managed successfully with intravenous lorazepam and other supportive measures. The 
patient was advised to strictly adhere to branched chain amino acid restricted diet.  
Conclusion 
This case report emphasizes on the importance of medication adherence and dietary restrictions to 
prevent permanent psychomotor damage or death. 
Key Words: GTCS, Genetic, MSUD, Seizures, Quadriplegia. 
 
 
*Please cite this article as: Satheesh G, Johnson S, Guhan B, Ahammed N. Maple Syrup Urine Disease Induced 
Grand Mal Seizures: A Case Report. Int J Pediatr 2018; 6(7): 7999-8002. DOI: 
10.22038/ijp.2018.31454.2782 
 
 
 
 
 
 
 
  
                                                 
*Corresponding Author: 
Gautam Satheesh, Department of Pharmacy Practice, National College of Pharmacy, Calicut, Kerala, India. 
Postal code: 673602. 
Email: gautamsatheesh@gmail.com  
Received date: Feb.21, 2018; Accepted date: Mar. 22, 2018      
GTCS Maple Syrup Urine Disease 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                            8000 
1- INTRODUCTION 
      Maple Syrup Urine Disease (MSUD) is 
a rare autosomal recessive error in 
metabolism of amino acids caused by the 
deficiency of branched-chain alpha-keto 
acid dehydrogenase complex enzyme 
system (BCKDC). This enzyme deficiency 
leads to the abnormal metabolism of 
branched chain amino acids and 
subsequent accumulation of leucine, 
isoleucine and valine as well as their 
corresponding keto acids in the blood and 
urine, resulting in the characteristic fruity 
odour (1). This deficiency can be caused 
by mutations in three genes which encode 
the catalytic components of the BCKDC 
(E1α, E1β, E2, and E3); namely BCKDHA, 
BCKDHB and DBT genes (Table.1). 
Mutation in E3 component (DLD gene) on 
chromosome 7q31 causes a severe 
condition termed as MSUD3, the 
symptoms of which vary from severe 
neonatal lactic acidosis to liver disorder, 
and generally subside with age. These 
homozygous or heterozygous mutations 
lead to defective oxidative decarboxylation 
of the branched chain amino acids (1). 
MSUD is rare in most populations, with 
incidence estimates of 1 in 185,000 live 
births globally (2, 3). Five phenotypes of 
MSUD have been recognized so far; 
classic, intermediate, intermittent thiamine 
responsive and MSUD3. Classic 
phenotype is the most common and most 
severe phenotype. While seizure is a 
common presentation in the neonatal stage 
in classic MSUD, development of seizures 
is often delayed and insidious in 
intermediate MSUD. Seizures are mostly 
generalized or focal; however status 
epilepticus may develop, requiring 
immediate intervention (3). 
 
Table-1: Genetic description of MSUD. Note that mutations in E1 and E2 components may result in 
any of the phenotypes except MSUD 3 which is specific to E3 component. 
Gene Involved Chromosome Comments 
Most Commonly 
Associated Phenotype 
BCKDHA 
 
19q13.1-q13.2 
In Mennonite population, asparagine 
commonly replaced tyrosine at position 
438 
Severe classic MSUD 
BCKDHB 6q14.1 
In Ashkenazi population, proline 
commonly replaced asparagine at 
position 183 
Severe classic MSUD 
DBT 1p21.2 
>70 mutations identified, frequent in 
mild variants of the disease (delayed 
onset of symptoms) 
Intermediate and 
intermittent MSUD 
DLD 7q31 
Mutation in E3 component i.e. DLD 
deficiency results in severe neonatal 
disorder. 
MSUD 3 
MSUD: Maple Syrup Urine Disease; BCKDC: Branched Chain α-Keto-acid Dehydrogenase Complex; DLD: 
dihydrolipoyl dehydrogenase. 
 
2- CASE REPORT 
     A fourteen year old female patient, 
previously diagnosed with intermediate 
MSUD, was admitted to a teaching 
hospital in Kerala, India, with multiple 
episodes of grand mal and rigidity of upper 
and lower limbs. Each episode was 
associated with oculogyric crisis and 
involuntary micturition. The patient has a 
history of dystonia of both limbs and 
spastic quadriplegia. The patient has been 
undergoing oral Levetiracetam therapy 
since the age of 5 after the first episode of 
seizure. The patient is the fifth child of a 
third degree consanguineous marriage. 
Two of the patient’s elder siblings, a male 
and a female, died at the ages of 9 months 
Satheesh et al. 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                            8001 
and 2 years, respectively; of which the 
female sibling was diagnosed with classic 
MSUD on post-natal day 8. Neurological 
examinations revealed dynamic 
contractures and brisk knee jerks. Routine 
laboratory investigations were well within 
normal limits. Developmental evaluation 
revealed regression of milestones and 
global developmental delay. The patient 
was found to have a Grade III stunt. 
Anthropometric measurement of head 
circumference revealed microcephaly. The 
fruity odour characteristic of MSUD was 
easily observable within the close 
proximity of the patient. Estimation of 
plasma proteins showed elevated leucine 
(946 μmol/L), isoleucine (302 μmol/L), 
and valine (602 μmol/L). Seizures were 
managed with anticonvulsants and other 
supportive measures. Initially, Lorazepam 
was administered intravenously followed 
by Fosphenytoin infusion (loading dose of 
400 mg in 300 ml normal saline every 30 
minutes and then maintained at 50mg). 
The patient continued to receive 
Fosphenytoin therapy along with oral 
Levetiracetam for the entire hospitalization 
period of 5 days. Supportive measures 
included normal saline and oxygen 
administration with nebulization.  The 
patient was advised to strictly adhere to 
low protein and BCAA restricted diet. 
Further reviews suggested that the 
patient’s condition has significantly 
improved without any seizure recurrence 
following discharge.  
3- DISCUSSION 
      Classic MSUD is the most commonly 
observed (>80% of cases) and the most 
severe phenotype, presenting with emesis, 
seizures and encephalopathy. Classic form 
develops early (by second week of life). 
However, in intermediate MSUD, typical 
signs i.e. developmental delay and seizures 
develop later. Subjecting an individual 
with intermediate MSUD to catabolic 
stress can cause severe leucinosis and even 
death. Other characteristic findings include 
ketoacidosis and dystonia
 
(1). Age of onset 
is a key factor of phenotype determination. 
The deficiency of BCKDC is responsible 
for the accumulation of BCAA and their 
toxic metabolites in blood and urine.   
Among the 4 catalytic components of 
BCKDC (E1α, E1β, E2, and E3), E3 
catalytic component serves pyruvate 
dehydrogenase and α-ketoglutarate 
dehydrogenase. The underlying 
mechanism of seizures in MSUD can be 
explained by accumulation and 
neurotoxicity of leucine and its 
transamination product 2-ketoisocaproate.  
Conversely, accumulation of leucine 
primarily causes all the neurological 
manifestations. Elevated plasma levels of 
isoleucine causes the characteristic odour 
of MSUD. Interestingly, valine seems to 
play a very insignificant role in the 
pathogenesis (4). Proper compliance, 
appropriate management and strict dietary 
restrictions are the most important tools to 
prevent severe complications i.e. status 
epilepticus, psychomotor retardation and 
potentially fatal metabolic abnormalities, 
especially under stressful conditions
 
(5).  
Immediate treatment focuses on 
maintenance of adequate hydration, 
management of seizures and rapid 
elimination of BCAA. Peritoneal dialysis 
or hemodialysis is reserved for critical 
cases. Permanent damage can be prevented 
with timely management of manifestations 
and prevention of extensive ischemia. 
Prolonged elevation of amino acid levels 
in the brain during early developmental 
stages lead to permanent neurological 
dysfunction. Mental retardation and 
behavioural abnormalities are common in 
individuals older than twelve years, 
warranting use of neuroleptics
 
(6). The 
patient is obliged to follow the dietary 
restrictions for the entire lifetime. The diet 
is essential in normalizing the levels of 
BCAA in the body, thus preventing 
developmental or intellectual impairment. 
GTCS Maple Syrup Urine Disease 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                            8002 
Various synthetic formulas practically 
devoid of BCAAs have been developed. 
Avoidance of BCAA rich foods i.e. beef, 
soy, lentils and diary is beneficial. The risk 
of development of MSUD is 25% when 
both the parents are carriers of mutated 
gene. This risk is significantly higher in 
consanguineously married individuals. 
Incidentally, MSUD is more prevalent in 
countries like Saudi Arabia, India and 
Lebanon where consanguineous marriage 
is common 
[1]
. The carrier frequency is 1 in 
113 in Ashkenazi Jewish populations. A 
study conducted in Philippines reported 
that 1/3
rd 
of MSUD cases were attributable 
to consanguinity (7).  
4- CONCLUSION 
      Seizures are highly unpredictable in 
Intermediate MSUD. Failure to receive 
adequate intervention, often lead to 
permanent retardation, coma and death. 
Therefore, adherence to antiepileptic 
therapy as well as a low protein and 
BCAA restricted diet is crucial to prevent 
severe complications. It is also highly 
essential that the individuals, who are 
married consanguineously, receive 
appropriate education about the possible 
risks of genetic defects they may carry. 
5- ABBREVIATIONS  
 MSUD: Maple Syrup Urine Disease. 
 BCKDC: Branched Chain α-Keto-acid 
Dehydrogenase Complex. 
 DLD: Dihydrolipoamide 
Dehydrogenase. 
 BCAA: Branched Chain Amino 
Acids. 
6- CONFLICT OF INTEREST: None. 
7- REFERENCES  
1. Chuang DT, Shih VE. Maple syrup 
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2. Nellis MM, Kasinski A, Carlson M, 
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3. Lee WT. Disorders of amino acid 
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4. Morton DH, Strauss KA, Robinson 
DL, Puffenberger EG, Kelley RI. Diagnosis 
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5. Simon E, Flaschker N, Schadewaldt P, 
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Maple Syrup Urine Disease Induced Grand Mal Seizures: A Case Report

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Maple Syrup Urine Disease Induced Grand Mal Seizures: A Case Report

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