Mitochondrial respiratory chain complex IV deficiency presenting as neonatal respiratory distress syndrome

Abstract

A term girl infant delivered following foetal distress presented with early respiratory distress syndrome and lactic acidaemia. She subsequently underwent detailed investigation for primary lactic acidaemia and was identified as homozygous for the c.515A>G,p.(Tyr172Cys) missense variant in the LRPPRC gene. Variants in this gene are known to cause French-Canadian type Leigh syndrome. Both parents were confirmed to be heterozygous for this mutation. This is the first case report of mitochondrial respiratory chain complex IV deficiency presenting as foetal distress and neonatal respiratory distress syndrome.

Background

The combination of neonatal respiratory distress syndrome, persistent lactic acidaemia and dysgenesis of corpus callosum should prompt consideration of mitochondrial respiratory chain complex IV deficiency.

Early evaluation may be beneficial for a timely diagnosis, appropriate involvement of the nutrition and metabolic team alongside genetic counselling.

Case presentation

The patient is the second infant born to consanguineous (second-degree) Middle-Eastern parents. Their first pregnancy resulted in a live boy born by C-section with an uncomplicated neonatal course. This older sibling is now 4 years of age and meeting expected milestones with no medical concerns. The couple has not experienced any foetal losses.

There were no antenatal concerns with the patient. The mother went into labour spontaneously at a gestational age of 38 weeks and 3 days. The patient is a term girl infant born via vaginal delivery assisted with forceps due to prolonged decelerations and foetal bradycardia suggesting foetal distress. She was born in good condition with a head circumference of 33.5 cm (9th–25th centile) and weighing 2.545 kg (9th centile). Though her Appearance, Pulse, Grimace, Activity and Respiration (APGAR) scores were 9 at 1 min and 10 at 5 min, the umbilical-cord blood gas showed an arterial pH level of 7.22, pCO₂ 7.72 kPa, base excess −4.2 and lactate 7.2 mmol/L. Consequently, the patient was reviewed by the neonatal team, and as the capillary blood gas confirmed an isolated high lactate level of 11.4 mmol/L, she was admitted to the neonatal unit. Her work of breathing increased and she was placed into incubator oxygen. Unfortunately, she began to show further signs of respiratory distress requiring continuous positive airway pressure (CPAP), and she was screened for sepsis alongside inherited metabolic disorders.

The patient was gradually weaned off CPAP by 3 days of life, after which she was comfortably self-ventilating in air with no concerns. Feeds were slowly introduced, but with each feed, she continued to develop signs of respiratory distress and lactic acidaemia requiring reliance on intravenous fluids.

The patient was extensively investigated for her raised lactate levels. Initial results from the metabolic screen highlighted an abnormal plasma acylcarnitine profile. Although the free carnitine level was normal 31 μmol/L (reference 15–53 μmol/L), there was a significant elevation of most plasma acylcarnitine species: C3 2.53 μmol/L (reference <1.3 μmol/L), C4 1.12 μmol/L (reference <0.4 μmol/L), C6 0.36 μmol/L (reference <0.12 μmol/L), C8 0.39 (reference <0.22 μmol/L) and C10 0.95 μmol/L (reference <0.30 μmol/L) to list a few. This was thus indicative of a more generalised mitochondrial dysfunction.

On day 7 of life, an ultrasound of cranial contents suggested ventriculitis with intraventricular adhesions, lenticulostriate vasculopathy and dysgenesis of the corpus callosum. An MRI brain confirmed dysgenesis of the corpus callosum together with small bilateral optic nerves. In combination with the lactic acidosis, hyporotation of hippocampus and appearance of periventricular cysts, these findings implied a diagnosis of pyruvate dehydrogenase complex deficiency (PDCD), a neurometabolic disorder presenting with neonatal lactic acidosis.

After discussions with the metabolic specialists and dietitians, the patient was then converted onto a ketogenic diet regimen of the ratio 90:10 ketocal:aptamil with the rationale to use fat instead of carbohydrate as the key source of energy. After a total of 7 weeks and 3 days on the unit, she had begun to feed well but was failing to thrive and weighed 3 kg (0.4th centile). As a result, a community discharge plan with regular dietetic review and blood glucose and ketone monitoring was put into place. Due to the suggested PDCD diagnosis, a skin and muscle biopsy were also taken to further investigate the possibility of an underlying mitochondrial disorder. The patient was to be followed up by the genetics, metabolic and neonatal team.

Unfortunately, after spending a month at home, at age two and a half months, she was readmitted to hospital with respiratory distress and vomiting. Her blood gas confirmed lactic acidaemia and she received bicarbonate therapy. After dietitian review, she was discharged and continued on the ketogenic diet. Regrettably, she had another similar episode at age three and a half months.

Throughout, the patient was thoroughly reviewed by the metabolic team. As the histology report of the muscle biopsy showed only subtle evidence of mitochondrial disorder, a mitochondrial respiratory chain enzymology was suggested. Biochemical analysis of in vitro enzyme uptake of the unit citrate synthase on skeletal muscle sample showed a reduced uptake of 0.249 nmol (mean 1.124 nmol±SD 0.511 nmol) by complex IV. Mitochondrial complex IV deficiency (MT-C4D) was confirmed on the basis of her clinical presentation, laboratory findings of lactic acidosis, progressive myopathy and MRI brain abnormalities suggestive of Leigh’s mitochondrial disorder. Additionally, further investigations proved negative for PDCD. Consequently, the regional mitochondrial team began extensive genomic sequencing to try to verify the genetic mutation responsive for the patient’s clinical findings. Whole-exome sequencing found her to be homozygous for a novel c.515A>G,p.(Tyr172Cys) variant in the LRPPRC gene with both parents heterozygous for this variant. Using the ensemble variant effect predictors, this variant is predicted to be deleterious by both SIFT and PolyPhen2. This variant is seen in GnoMAD, with an allele frequency of 0.00005177 (ie, <0.01). There are 14 uploads out of a total of 383 490 exome/genomes; however, none of these are reported in the Middle-Eastern population.

The patient was regressing in her developmental milestones. She showed progressive hypotonia, unable to fix and follow objects and developed swallowing difficulties. Her weight had dropped to 2.89 kg (below the 0.4th centile), thus the nutrition team recommended sole nasogastric tube feeding. She was also weaned onto a more conventional feeding regimen of Infatrini Peptisorb alongside ubiquinone.

Over this period of transition, the patient was admitted to hospital following a blue episode which required cardiopulmonary resuscitation (CPR). Although a chest X-ray showed signs of pulmonary oedema and respiratory infection, an echocardiogram confirmed normal cardiac function. A nasopharyngeal swab was positive for adenovirus. Over the 2 weeks, she suffered several apnoeic episodes and severe lactic acidosis resulting in intubation and ventilation. After several discussions with her metabolic consultant, it was agreed with her parents that, at 4 months of age, she was ready for extubation and if she were to deteriorate again, it would not be in her best interest to reintubate. A do-not attempt CPR form was agreed on and signed, after which she was then extubated onto high flow oxygen which was gradually weaned to low-flow nasal-prong oxygen.

Investigations

Ultrasound of cranial contents (day 7 of life)

Suggestive of ventriculitis with intraventricular adhesions, lenticulostriate vasculopathy and dysgenesis of the corpus callosum.

MRI brain

Accentuated dysgenesis of the corpus callosum together with small bilateral optic nerves.

Muscle biopsy histology report

Very subtle abnormality, possible appearance of mitochondrial disorder, respiratory chain enzymology needed.

Skeletal muscle sample

Significant mitochondrial respiratory chain defect involving complex IV, demonstrated by the biochemical analysis of in vitro enzyme activity.

Whole-exome sequencing

Homozygous for the c.515A>G,p(Tyr172Cys) variant in the LRPPRC gene.

Parent whole-exome sequencing

Both found to be heterozygous for the c.515A>G,p(Tyr172Cys) variant in the LRPPRC gene.

Differential diagnosis

• PDCD.

• Leigh’s mitochondrial disorder.

• MT-C4D.

Outcome and follow-up

The patient was transferred to Rainbows Hospice for care. She initially tolerated her feeds through nasogastric tube until, at age 7 months, she was readmitted to hospital for aspiration pneumonia. Unfortunately, she did not survive this episode.

Discussion

This is the first case report of this specific genetic mutation in the LRPPRC gene causing MT-C4D presenting as neonatal respiratory distress.

MT-C4D (cytochrome c oxidase) is one of the most common respiratory chain defects affecting human beings.¹ This terminal enzyme of the respiratory chain consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA.² The novel genetic mutation appears to present initially with foetal distress during labour and subsequently lactic acidosis and neonatal respiratory distress, indicative of an impaired mitochondrial function mainly affecting the respiratory system.² The c.515A>G,p(Tyr172Cys) variant also appears to be inherited similarly as an autosomal recessive disorder.

Although MT-C4D can vary clinically from isolated myopathy to severe multisystem disease in either infancy or adulthood,² our case presentation emphasises a neonatal onset. There are four main types of the disorder differentiated by symptoms and age of onset; benign infantile mitochondrial type, French-Canadian type, infantile mitochondrial myopathy type and Leigh syndrome.¹ The latter is a neurodegenerative disorder characterised by bilateral high signal lesions in the brainstem and basal ganglia. The French-Canadian variant of cyclo-oxygenase (COX) deficient Leigh syndrome (LSFC) is caused by a founder mutation [c.1061C>T,p.(Ala354Val)] in the LRPPRC gene and unique to Saguenay-Lac-Saint-Jean region of Quebec, Canada.³ These patients present with intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration, similar to our case. There have been reported cases of different genetic variants resembling similar clinical phenotypes outside of this region.⁴ However, these patients have additional problems of mild hypertrophic cardiomyopathy, congenital malformations, seizures and microcephaly to name a few.³ It could be the unique mutation of our case described presents as neonatal respiratory distress, adding to the complications of the deficiency.

As LSFC patients are the largest known cohort with a genetically homogeneous, nuclear encoded congenital lactic acidosis studied,¹ further investigation is required into the new phenotypically distinct forms of Leigh syndrome caused by different mutations in the LRPPRC gene. Nevertheless, there is a similar case presentation to the above described by Bakker et al; a newborn presenting with tachypnoea, feeding difficulties, severe lactic acidosis and a high pyruvate level.⁵ It could be hypothesised that certain genetic mutations could thus present initially with an elevated pyruvate kinase level, which could be used as an indicator for further investigation into Leigh’s syndrome.

There is no cure for MT-C4D, simply supportive management.¹ The prognosis varies according to the form present and can be influenced by other genetic and/or environmental factors.² There appear to be overlapping trends in certain phenotypes which could be used as a trigger for earlier investigation into Leigh syndrome.³ As our case report presents a unique mutation in the LRPPRC gene presenting as foetal distress and neonatal respiratory distress, we can use this alongside the findings of lactic acidosis and initial elevated pyruvate levels with MRI brain changes to consider Leigh syndrome as a differential diagnosis earlier on in the management plan.

Patient’s perspective.

Parent’s perspective: we feel our daughter was well looked after with all aspects of her care within all departments in Leicester. All the staff treated us as a whole and incorporated all our wishes and desires. We felt listened too and happy with the care we received. We are eager for this case report to be shared with others to help with early diagnosis and relevant management plans for other babies that may be in a similar situation as our daughter.

Learning points.

• LRPPRC mutation is a rare cause of the mitochondrial complex IV (cytochrome c oxidase) deficiency form of Leigh syndrome outside of Quebec.

• There are reported cases of novel mutations broadening the spectrum of phenotypes of Leigh syndrome.

• Our patient expands on these findings, presenting initially with foetal distress, neonatal respiratory distress syndrome and lactic acidaemia.