Introduction
TMEM70 deficiency is a rare autosomal recessive disorder that causes mitochondrial complex V deficiency, nuclear type 2. TMEM70 is inner mitochondrial membrane localized transmembrane protein where it functions to stabilize ATP synthase. The main features of TMEM70 deficiency include a neonatal or infantile onset of cardiomyopathy, hypotonia, poor feeding, heart failure, and poor growth with an associated hyperammonemia, lactic acidosis, and 3-methylglutaconic aciduria. Repeat metabolic crises are known to occur with majority of mortality occurring within 5 years of age.

Case Presentation
We present a now 7 year old male with a diagnosis of TMEM70 deficiency. The patient first presented on day 2 of life with dysmorphic facial features, respiratory failure requiring ventilator support and noted pulmonary hypertension with severe tricuspid regurgitation, increasing lactic acidosis, and hyperammonemia. Prenatal history significant for intrauterine growth restriction. Lactic acidosis and hyperammonemia corrected quickly with IV fluid support within the first week of life. Respiratory support weaned by DOL6. MRI/MRS brain performed noted abnormal T2 signal in the brainstem, diencephalon, and basal ganglia with associated lactate peak. Repeat echocardiogram on DOL8 noted improved pulmonary hypertension and new biventricular hypertrophy.

Diagnostic Workup
The patient was noted to have lactic acidosis that quickly corrected by DOL 6 (peak 16.6 mmol/L) with hyperammonemia (peak 210 µmol/L) that rapidly corrected without use of ammonia scavengers. Acylcarnitines normal. Amino acids with multiple elevations most notably elevated alanine (2150 µmol/L) and glutamine (2086 µmol/L). Urine organic acids with significant lactic acid and ketoacids, no 3-methylglutaconic aciduria noted. Multi-gene panel for disorders for lactic acidosis/pyruvate metabolism resulted with homozygous pathogenic variant in TMEM70: c.317-2A>G (reported consanguinity).

Treatment and Management
Management focused on supportive care during initial presentation with IV fluid and caloric support. Further management included multi-specialty care including continued follow-up with cardiology and gastroenterology due to poor feeding.

Outcome and Follow-Up
The patient had several repeat episodes throughout infancy of metabolic crisis with lactic acidosis and hyperammonemia typically during intercurrent illness. His admissions decreased over time. Pulmonary hypertension resolved by 28 months of age. Biventricular hypertrophy improved and normalized by 7 years of age. He developed ascending aortic dilation around 3.5 years that has been persistent, but stable with Z-score 5. He had continued difficulties with feeding and dysmotility, noted to have malrotation requiring Ladd’s procedure and gastrostomy tube placement. Over time, the poor feeding improved and eventually taking all food by mouth by 7 years of age. Branchial cyst excision at 6 months. His developmental course is consistent with global developmental delay and diagnosis of autism spectrum disorder level 3 at age 4. Continues to make developmental progress without regression and is supported with extensive ABA and other therapies.

Discussion
TMEM70 deficiency is a rare disorder characterized by neonatal crises and cardiomyopathy. Here we report on a case with an extended natural history including in-depth neurodevelopmental data with typical features of TMEM70 deficiency alongside uncommon features with aortic dilation, malrotation, and branchial cyst. Nonprogressive cardiomyopathy is a commonly reported finding and noted to be regressive in some patients. The patient presented here displayed a similar course with improvement in his ventricular hypertrophy, but has developed aortic dilation, a very rarely described complication. Despite multiple complications, he responded well to standard management and has survived beyond the mortality peak by age 5. This case highlights the importance of early detection given risk for neonatal metabolic crisis that responds to caloric support and reversal of catabolism, and early detection of cardiomyopathy.

Conclusion
This presents insight into long-term complications in TMEM70 deficiency and adds to the limited reported natural history of the disease. This case additionally presents clinical information for potential expansion of the phenotype with aortic dilation, malrotation, and branchial cyst.