Introduction
Methylmalonic acidemia (MMA) is a biochemical hallmark of a genetically heterogeneous disorder of vitamin B12 metabolism. The incidence of MMA is estimated as 1/50,000.1 According to phenotype, two main types have been identified, isolated MMA and combined MMA with homocystinuria. Isolated MMA is due to defects of methylmalonyl -CoA mutase (MCM) or the synthesis of adenosylcobalamin (AdoCbl), while combined MMA with homocystinuria, is characterized by raised plasma homocysteine and reduced levels of AdoCbl and methylcobalamin (MeCbl), which lead to decreased activity of the enzymes MCM and methyltetrahydrofolate–homocysteine methyltransferase, or methionine synthase respectively.2
Combined MMA and homocystinuria is a genetically heterogeneous disorder, instigated by inborn errors of cobalamin metabolism. Different types of the disorder have been classified, based on the gene involved: cblC, cblD, cblF, cblX, cblJ and cblC being the most common subtype. Type CblC is caused by a mutation in the MMACHC gene on chromosome 1p34. Type cblD in which, the mutation in the MMADHC gene on chromosome 2q23, which has a role in directing cobalamin to the two cobalamin-dependent enzymes, MCM and Methionine synthase. Type cblF is caused by mutation in the LMBRD1 gene, located on chromosome 6q13. Type cblX is an X-linked recessive metabolic disorder, caused by mutation in the HCFC1 gene on chromosome Xq28, mutations of which inhibit its function in the transcriptional activation of MMACHC. Type cblJ is caused by a mutation in the ABCD4 gene on chromosome 14q24, which is tangled in the lysosomal release of cbl into the cytoplasm. Mutation analysis is not only the gold standard in the diagnosis of MMA but also helps in the choice of treatment strategy, B12 responsive or unresponsive.2 Further, the incidence of combined MMA with homocystinuria cblD & cblF types is estimated as less than 1: 100,000.3
The clinical manifestations of combined MMA with homocystinuria vary, but classically include neurologic, developmental and hematologic abnormalities in children. 4
The onset of manifestations of MMA, ranges from the neonatal period to adulthood. All phenotypes reveal, sporadic periods of relative health and metabolic decompensation, usually related to intercurrent infections and stress. In the neonatal period, the disease may present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonaemia, neutropenia, and thrombocytopenia, and can lead to death at a very young age.5 In adults, the presentation may be recurrent epileptic seizures, dizziness, schizophrenia and other mental disorders. 6
Case Report
The child at the age of 10 months, presented with complaints of poor feeding, delayed growth and no neck holding/ head control (milestone normally present at 3-4 months) in paediatric OPD and was admitted at tertiary care centre *********. He was managed conservatively and evaluated for amino acid profile & acyl carnitine profile based on LC-MS. He had recurrent hospital visits for poor growth, global developmental delay and weakness in both lower limbs at the same hospital. He was on regular follow-up at Pediatric OPD and further evaluated for possible causes of metabolic disorder (NGS and Sanger sequencing) and diagnosed as a case of MMA with Homocystinuria. Subsequently, this child developed weakness in all four limbs along with respiratory failure and he was admitted to PICU at the tertiary care centre *****.
Investigations
Hb: 9 gm/dL
TLC: 13,700 cells/mm3 Neutrophils: 79.5 %, Lymphocytes: 13.6 %, Monocytes: 6.9 %
RDW: 18.4 %, MCV: 82.8 fL, MCH: 23.9 pg, Platelets: 4.3 lacs,
Vitamin B12: 108 pg/mL (normal range: 190-950 pg/mL)
Sr Urea: 20 mg/dL, Sr. creatinine: 0.5 mg/dL, Sr electrolytes: Na-146 mEq/L,
K- 4.3 mEq/L, Total Bilirubin: 0.2 mg/dL, Direct Bilirubin: 0.1 mg/dL, Total protein: 7.9 g/dL, Albumin: 4.3 g/dL, Globulins:4.6 g/dL, ALT: 22 IU/L, AST: 23 IU/L,
Urine exam: normal.
ABG analysis: suggested compensatory respiratory acidosis.
Table 1
Clinicalexome sequencing report analyzed by sanger sequencing
Investigations were done to rule out metabolic disorders
-
LC-MS on DBS (dried blood spot):
NGS and Sanger sequencing: Table 1.
The child was managed with:
Low protein diet
IV antibiotics
Nebulization with 3% saline and levosalbutamol 4hrly
Syp carnitine 3.5 ml 12 hrly for 4 weeks then stopped
Tab. Thiamine 50 microgram once a day
Injection vitamin B12 (hydroxocobalamin) 50 microgram i.m. once in 04 weeks.
During hospitalization, he was placed on mechanical ventilation via endo-tracheal (ET) intubation and within 4 weeks, he had vocal cord paralysis and recurrent block of ET tube by copious mucus secretions, for which tracheostomy was done. He could not swallow (due to neuromuscular weakness) and hence, underwent percutaneous endoscopic gastrostomy (PEG) for enteral feeding (nutrition) as well as administration of medicine.
The child remained on supportive treatment with inj. Celecel (contain trace elements), Vitamin B12 and Syrup multivitamin, 150 mL feeds- 3 hrly through PEG and palliative care in PICU, kept on mechanical ventilation via tracheostomy in situ. Unfortunately, the child did not respond to treatment and succumbed to death, despite all resuscitative measures.
Discussion
Patients with MMA experience significant morbidity and mortality, and prognosis for long term survival is poor. There is a real challenge for a specialist, treating the case of a child with neurological manifestations and poor outcomes, despite the best medical care modalities. The children affected by MMA usually exhibit anorexia, failure to thrive, hypotonia, developmental delay, progressive renal failure, functional immune impairment, optic nerve atrophy, and hematologic abnormalities.2
However, the child developed global developmental delay with quadriparesis, which suggest predominant neurological manifestations, but these findings are very different from a study carried out by Jinrong Liu et al. which showed that the children predominantly present with late-onset diffuse lung disease and pulmonary arterial hypertension.4 Hence, our study has categorized variable phenotypes of neurodevelopment in early-treated cblD and cblF patients diagnosed based on liquid chromatography- mass spectrometry (LC-MS) and Next Generation Sequencing (NGS) validation by Sanger sequencing. The long-term outcomes of cblD & cblF types of MMA with homocystinuria remain unsatisfactory and unresponsive to B12 supplements. The neurological manifestations and global developmental delay of variable severity may always be present, irrespective of age at diagnosis or treatment onset and the same, we had observed in this child. Moreover, all the patients suffering from MMA, often present with poor growth, feeding problems and seizures.7
Conclusion
This case report has categorised, variable phenotypes of MMA along with homocystinuria of cblD and cblF types in a child, which is a very rare metabolic disorder of cobalamin metabolism presented with neuro-developmental complications. The diagnosis is based on mutation analysis by next-generation sequencing (NGS), and validation by Sanger sequencing. The long-term outcomes of cblD & cblF MMA with homocystinuria remain unsatisfactory and have poor prognosis despite best-known treatment modalities. The apt diagnosis and adequate treatment at an early stage may improve the prognosis in responsive cases. It was observed that the child presented at 10 months of age, so it can be due to decreased B12 levels in mothers. Hence, maternal awareness as well as screening for Vitamin B12 deficiency during pregnancy is recommended and advised to estimate Vitamin B12 levels in mothers. This report aims to create awareness about very rare clinical presentations associated with cblD & cblF types of combined MMA with homocystinuria and the need for early diagnosis, to establish an outline for the treatment in these patients.
