Glutaric aciduria II (GA2, OMIM # 231680), also called
multiple acyl-coenzyme A (acyl-CoA)
dehydrogenase deficiency (MADD), is an autosomal recessive inborn error
of fatty acid, amino acid, and choline metabolism. The prevalence rate of MADD
is 1 to 9/1,000,000 but there is a great variation among different countries.1 Based on the Philippine Pediatric Society registry and
as confirmed with the Institute of Human Genetics which manages the metabolic
registry (oral communication, May 2019), this is the
first reported case in the Philippines. 2 Three genes are involved
in glutaric acidemia type II, namely ETFA (15q23-q25), EFTB
(19q13.3-q13.4) and ETFDH (4q32-q35).
Symptoms result from deficiencies in the electron transfer flavoprotein
(ETFA or ETFB subunits) or ETF flavoprotein dehydrogenase (ETFDH) seen in the
inner mitochondrial matrix, which are essential in metabolizing proteins and
There are three described phenotypes of
MADD -- neonatal onset with, or without, congenital anomalies (MADD-S, severe),
and mild and/or late onset (MADD-M, mild).
Classical MADD or MADD-S may present with hypoglycemia, hyperammonaemia
and acidosis with hypotonia and hepatomegaly in the early life. Congenital
abnormalities involving the kidneys, genitalia and neuronal migration defects
are noted in infancy yielding a poor prognosis. MADD-M patients manifest in
adolescence or adulthood with acute Reye-like illness with ketoacidosis and
lipid storage myopathy triggered by infections or fasting, and are associated
with better outcomes. Some mutations in
the ETFDH gene have been associated
with riboflavin-responsiveness. The ETFDH
(or ETFQ:O) protein mediates electron transport from flavoprotein
dehydrogenases to the ubiquinone pool.6 Riboflavin
is a precursor of flavin adenine dinucleotide (FAD), a cofactor of ETFDH, hence
riboflavin has been hypothesized to play a role in proper protein folding or
stabilization of ETFDH variant protein conformation.7
case report describes a school-aged child with clinical manifestations and
molecular confirmation consistent with mild, riboflavin-responsive MADD.
A previously healthy 9-year-old Filipino
male presented with encephalopathy and lower extremity weakness. He had a
3-week history of multiple bouts of loose bowel movement and vomiting with
resolution after hydration and antibiotic therapy. He developed undocumented
fever, severe abdominal pain, bilateral lower extremity weakness, and decreased
sensorium a few hours prior to admission. Complete blood count revealed
leukocytosis with neutrophilic predominance. Serum lactate dehydrogenase
(10,307 U/L), serum aspartate aminotransferase (AST; 5,295 U/L), serum alanine
aminotransferase (ALT; 830 U/L), and serum ammonia (152 umol/L) were
significantly elevated. Hypoglycemia was noted on capillary blood glucose
testing. At the time, the impression was acute liver injury probably secondary
to ischemia, rule out Reye syndrome. He was transferred to our institution for
further work-up and management.
He is the younger among 2 children, born
to non-consanguineous parents of Filipino descent. Family history of fatty
liver on the maternal side and of diabetes mellitus on both maternal and
paternal sides were noted. The rest of the history was non-contributory.
At the emergency room, the patient was
received stretcher-borne, drowsy but arousable, not in cardio-respiratory
distress. The patient was afebrile, normotensive, had tachycardia with regular heart rhythm, and clear breath
sounds. There was no jaundice noted. Abdominal examination revealed epigastric
tenderness on light palpation with palpable liver edge 1-2 cm below the
subcostal margin. He had no cranial
nerve and sensory deficits but there was significant symmetric muscle weakness
with motor grading of 3/5 in all extremities. Meningeal signs were absent.
Imaging studies such as cranial computed
tomography scan and chest X-ray were unremarkable. Serum ceruloplasmin, antinuclear antibodies,
immunoglobulin G, anti-smooth muscle antibody, and anti-liver-kidney microsomal
antibody were within normal limits. He had rhabdomyolysis with a peak creatine
kinase (CK) level of 50,842 U/L (elevated 726-fold). Serum aminotransferases
(AST significantly higher than ALT) and lactic dehydrogenase were
elevated. Urine organic acid analysis
revealed a moderately increased adipate with slightly increased decenedioate
and suberate, and positive hexanoylglycine and suberylglycine, suggestive of a
fatty acid oxidation disorder. Due to unavailability of plasma acylcarnitine
analysis during this time, tandem mass spectrometry analysis of dried blood
spot samples was done which showed an increase in medium chain and very long-chain
acyl-CoA dehydrogenase metabolites namely decanoylcarnitine (C10),
dodecanoylcarnitine (C12), and ratios of octaboylcarnitine/acetylcarnitine
(C8/C2) and tetradecenoylcarnitine/acetylcarnitine (C14:1/C2).
The initial consideration was a fatty acid
oxidation disorder, probably very long chain acyl Co-A dehydrogenase deficiency
on the basis of the clinical presentation of acute muscle weakness,
rhabdomyolysis precipitated by a history of acute gastroenteritis, high ammonia
and organic acid analysis results.
The patient received aggressive hydration
with 5% dextrose in 0.9% normal saline, with frequent monitoring of CK
levels. Adequate caloric support was
provided through nasogastric tube feeding.
By the 5th hospital day, his sensorium
improved, he regained his motor strength and his CK had decreased to 657 U/L.
Other abnormal laboratory parameters also gradually normalized. He was
eventually discharged well and advised lifestyle and diet modification, as well
as avoidance of fasting and special precautions to increase caloric intake
during exercise or episodes of concomitant illness. A fatty acid oxidation disorder
panel was sent (Invitae, USA), and sequence analysis and deletion/duplication
testing of the 31 genes tested revealed a homozygous pathogenic variant,
c.250G>A (p.Ala84Thr) identified in ETFDH
gene, confirming the diagnosis of Glutaric Aciduria type II.
He was advised to start a healthier diet
with fat content at the recommended intake for his age, and was started on
Riboflavin 300 mg/day and CoQ10 60 mg/day.
They were also advised regarding avoidance of fasting, early consult and
higher calorie intake during sick days.
Genetic counseling was done regarding recurrence risk for autosomal
recessive inheritance. Twelve months
since his presentation to the emergency room, he has been asymptomatic with no
recurrence of muscle weakness.
Rhabdomyolysis is defined as muscle
symptoms with 11-fold increase of serum creatine kinase. Biochemically, an insult in the ion
channels can activate a series of myolytic cascading events leading to necrosis
of the muscle fibers and release of its contents such as myoglobin, creatine
kinase, aldolase, and lactate dehydrogenase into the bloodstream. The causes of rhabdomyolysis overlap with that
of muscle weakness and may range from traumatic injury to infectious and
genetic etiologies. When initial testing for common acquired causes does not
reveal a diagnosis, inherited myopathies should be
considered and these include inborn errors of metabolism such as glycogen
storage disorders, fatty acid oxidation disorders, and mitochondrial disorders,
as well as congenital myopathies and mutations in LPIN1.8
tests such as urinary organic acid analysis and plasma acylcarnitines aid in
the diagnosis of metabolic myopathies. For patients with MADD, urine organic
acid analysis findings show combinations of increased dicarboxylic acids,
glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates,
similar to the findings in our patient.5 The plasma acylcarnitine
profile may reveal short, medium and long chain metabolites.4 Muscle biopsy, now
recommended only when genetic test results are inconclusive, may show lipid
accumulation and enlargement of the mitochondria.8 Molecular DNA testing can confirm the diagnosis and
in our case was very informative in terms of predicting prognosis.
c.250G>A (p.Ala84Thr) variant identified in ETFDH gene in our patient has been reported as the most common mutation in
late-onset/ riboflavin-responsive MADD and is common in South East Asian
countries like Southern China and Taiwan where there is a strong Southern Min
background.9,10,11 Chen, Zhang et. al. proposed that the geographic
distribution of the variant being consistent with the migration route of the
southern Min Chinese in Southeast Asia is suggestive of a founder effect in
this population. While this patient does
not have any reported Chinese ethnicity, the Philippines actually has a
significant number of Chinese immigrants, wherein 98.1% are of Min background,
and majority specifically from Quanzhou.12 The usual dose of
riboflavin supplementation reported for riboflavin-responsive patients is
90-400mg/day, which results in significant improvements in the biochemical and
clinical parameters as seen in our patient.
It is important to have a high index of
suspicion for metabolic disorders in patients with unusual presentations such
as encephalopathy and rhabdomyolysis. Prompt and correct diagnosis will enable
us to give appropriate intervention and prevent future episodes of
life-threatening rhabdomyolysis. The availability of diagnostic panels is
helpful in narrowing down possible metabolic causes in a timely manner when it
is difficult to identify the specific enzyme defect. This case further supports the good genotype
phenotype correlation in MADD and its importance in counseling regarding
outcomes and response to therapy.
The authors would like
to thank the Pediatric team of the Medical Center Manila (ManilaMed) for the
multi-disciplinary medical management
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(2006). Reading Chinese Transnationalisms: Society, Literature, Film. Hong Kong: Hong Kong University Press. p.20.