|Year : 2021 | Volume
| Issue : 1 | Page : 42-45
Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1
Ayush Agarwal1, Divyani Garg2, Sangeeta Agarwal3
1 Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
2 Department of Neurology, Lady Hardinge Medical College, New Delhi, India
3 Consultant Paediatrician, Lucknow, Uttar Pradesh, India
|Date of Submission||14-Jan-2020|
|Date of Decision||19-Sep-2020|
|Date of Acceptance||17-Oct-2020|
|Date of Web Publication||17-Apr-2021|
Dr. Divyani Garg
Department of Neurology, Lady Hardinge Medical College, New Delhi.
Source of Support: None, Conflict of Interest: None
Glutaric aciduria type 1 is an autosomal recessive disorder caused by mutations in GCDH gene on chromosome 19 leading to the deficiency of glutaryl-CoA dehydrogenase which causes an abnormal metabolism of lysine, hydroxylysine and tryptophan with resultant accumulation of glutaric acid and 3-hydroxy glutaric acid. Usual presentations include macrocephaly with recurrent dystonic episodes, along with developmental regression. The diagnosis is based on characteristic magnetic resonance imaging finding of widening of sylvian fissures and urinary tandem mass spectroscopic analysis of excess glutarylcarnitine and hydroxyglutaric acid. Management includes lysine-free diet and carnitine supplementation.
Keywords: Carnitine, dystonia, GA-1, glutaric, lysine, TMS
|How to cite this article:|
Agarwal A, Garg D, Agarwal S. Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1. Ann Mov Disord 2021;4:42-5
|How to cite this URL:|
Agarwal A, Garg D, Agarwal S. Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1. Ann Mov Disord [serial online] 2021 [cited 2022 Dec 1];4:42-5. Available from: https://www.aomd.in/text.asp?2021/4/1/42/313942
| Introduction|| |
Glutaric aciduria type 1 (GA-1) is an autosomal recessive disorder caused by mutations in GCDH gene on chromosome 19 leading to deficiency of glutaryl-CoA dehydrogenase. This engenders abnormal metabolism of lysine, hydroxylysine, and tryptophan with resultant accumulation of glutaric acid and 3-hydroxy glutaric acid., Usual presentation is macrocephaly at birth with recurrent episodes of dystonia (simulating seizures), along with developmental regression. Diagnosis is based on characteristic magnetic resonance imaging (MRI) finding of widening of sylvian fissures suggestive of “microencephaly in macrocephaly.” Urinary tandem mass spectroscopic (TMS) analysis reveals excess glutarylcarnitine and hydroxyglutaric acid. Management includes lysine-free diet and carnitine supplementation.
Although there are several case reports of GA-1 till date, there are very few reported sibships. We report one such instance of two siblings with GA-1 with varied manifestations.
| Case Report|| |
A 9-month-old girl, product of third-degree consanguineous marriage, born at full-term by normal vaginal delivery, presented with two episodes of fever associated with abnormal posturing of right upper limb with opisthotonus and forward chest thrusting lasting a few days from the age of 6 months. She had lost neck control (attained at 5 months) after the first episode.
Examination revealed macrocephaly (51cm), broad nasal root, hypertelorism, sparse hypopigmented hair, coarse skin and dystonic posturing of the right upper limb (hyperextension at elbow and clenched fist) [Figure 1]A. She also lacked neck control.
|Figure 1: (A) Patient with macrocephaly, broad nasal root, hypertelorism, sparse hypopigmented hair, coarse skin, and dystonic posturing of her right limb. (B) Elder sister with severe dystonic posturing of the neck, trunk and all four limbs along with severe contractures|
Click here to view
Routine investigations including complete blood count, liver and renal function tests, serum ammonia, and blood glucose were normal. Urine TMS revealed increased excretion of glutarylcarnitine. Electroencephalogram (EEG) was normal. MRI brain showed bilateral frontotemporal atrophy with open opercula and dilated sylvian fissures [Figure 2]A and [B]. This microencephalic macrocephaly is a radiological hallmark of this disorder. She was diagnosed to have GA-1 based on TMS and MRI findings.
|Figure 2: (A and B) MRI brain coronal T1 and axial T2-weighted images showing widening of sylvian fissures and open opercula|
Click here to view
Similar complaints were also present in her only other sibling, her 6-year-old elder sister, with onset at 8 months of age. Medical advice had not been sought for her till then. She had progressive worsening till 3 years of age, with a static course thereafter. She is now bed bound with persistent abnormal posturing of all limbs along with contractures [Figure 1B]. Her urine TMS also revealed increased excretion of glutarylcarnitine. MRI brain could not be done due to dystonic posturing and fixed contractures.
| Discussion|| |
GA-1 is an inborn error of metabolism of hydroxylysine, lysine and tryptophan due to autosomal recessive mutation of GCDH gene on chromosome 19, encoding for the mitochondrial enzyme glutaryl-CoA dehydrogenase. The resultant deficiency leads to accumulation of glutaric acid and 3-hydroxy glutaric acid. These are cytotoxic to the brain leading to neuronal damage and subsequent cerebral atrophy. Estimated prevalence is 1 in 56,000 with reports of siblings with GA-1 being exceedingly rare., We report the same in both daughters born from a third-degree consanguineous marriage.
The differentials considered were leukodystrophies that present in infancy with macrocephaly like Alexander’s disease, Canavan’s disease, and Megalencephalic leukoencephalopathy with subcortical cysts. However, these were ruled out based on neuroimaging and urinary TMS reports. Similar positive report in her afflicted sibling added further diagnostic certainty.
Patients usually present between 6 months to 2 years of age with acute neurological deterioration, following a febrile illness or even without a triggering event (10%–20% cases).,, Hypotonia develops 1–3 days after fever, attained milestones are lost and intermittent dystonic posturing episodes simulating seizures occur. Some improvement occurs following fever resolution, but baseline status is never attained. Hypotonia is replaced by persistent rigidity and dystonia. Our patient presented similarly with acute deterioration following a febrile episode with loss of head control, axial hypotonia, and limb dystonia.
Fever induces a catabolic state causing decompensation of the already damaged basal ganglia, leading to acute deterioration. Emergency treatment is therefore imperative. Symptomatic management of fever/ infections along with L-carnitine supplementation (100mg/kg body weight) and lysine-free/ decreased lysine diet are the treatment modalities. Treatment in presymptomatic state leads to best results with response thereafter depending on time elapsed since first presentation. These episodes have not been reported beyond 5 years of age, underscoring the need for early diagnosis and treatment to prevent irreversible sequelae. The older sibling had dystonia with fixed contractures, probably due to such repeated episodes.
MRI brain has additive diagnostic value. GA-1 has characteristic findings of cerebral atrophy with widening of sylvian fissures which has been reported in the literature as microencephalic macrocephaly., However, these are not entirely specific and should be followed by urine TMS analysis. Increased excretion of glutarylcarnitine clinches the diagnosis. Both siblings were positive for the same.
Our patient was provided symptomatic emergency care followed by L-carnitine supplementation and diet with decreased amounts of lysine with good results. She regained head control 4 weeks into treatment and is progressively attaining her milestones at last follow-up, 6 months from presentation.
The elder sister was treated symptomatically with tetrabenazine for her dystonia.
| Conclusion|| |
GA-1 is a rare but treatable cause of movement disorders presenting in infancy or early childhood. A high index of suspicion is imperative as treatment response wanes over time.
Ethical compliance statement
The study complied with all ethical standards and did not require the consent of the Institutional Ethics Committee. Written informed patient consent was taken. All authors have read and complied with the journal’s ethical publication guidelines.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Goodman SI, Stein DE, Schlesinger S, Christensen E, Schwartz M, Greenberg CR, et al
. Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): Review and report of thirty novel mutations. Hum Mutat 1998;12:141-4.
Hedlund GL, Longo N, Pasquali M. Glutaric academia type 1. Am J Med Genet C (Semin Med Genet) 2006;142C:86-94.
Strauss KA, Puffenbeger EG, Robinson DL, Morton DH. Type 1 glutaric aciduria, Part 1: Natural history of 77 patients. Am J Med Genet C (Semin Med Genet) 2003;121C:38-52.
Sen A, Pillay RS. Striatal necrosis in type 1 glutaric aciduria: Different stages in 2 siblings. J Paediatr Neurosci 2011;6:146-8.
Kimura S, Hara M, Nezu A, Osaka H, Yamazaki S, Saitoh K. Two cases of glutaric aciduria type 1: Clinical and neuropathological findings. J Neurol Sci 1994;123:38-43.
Brismar J, Ozand PT. CT and MR of the brain in glutaric acidemia type I: A review of 59 published cases and a report of 5 new patients. AJNR Am J Neuroradiol 1995;16:675-83.
Hoffmann GF, Zschocke J. Glutaric aciduria type I: From clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis 1999;22:381-91.
Pöge AP, Autschbach F, Korall H, Trefz FK, Mayatepek E. Early clinical manifestation of glutaric aciduria type I and nephrotic syndrome during the first months of life. Acta Paediatr 1997;86:1144-7.
Busquets C, Merinero B, Christensen E, Gelpi JL, Campistol J, Pineda M, et al
. Glutaryl-CoA dehydrogenase deficiency in Spain: Evidence of two groups of patients, genetically and biochemically distinct. Pediatr Res2000;48:315-22.
Nunes J, Loureiro S, Carvalho S, Pais RP, Alfaiate C, Faria A, et al
. Brain MRI findings as an important diagnostic clue in glutaric aciduria type 1. Neuroradiol J 2013;26:155-61.
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, et al
. Diagnosis and management of glutaric aciduria type 1––revised recommendations. J Inherit Metab Dis 2011;34:677-94.
[Figure 1], [Figure 2]