Expanding and Underscoring the Hepato-Encephalopathic Phenotype of QIL1/MIC13

Mitochondrial disease can present with rapid infantile liver failure. Two sibling pairs with variants in QIL1, a gene important for mitochondrial contact site and cristae organizing system (MICOS) function, were recently reported on. They had intermittent liver disease, mild cardiac hypertrophy, cerebellar atrophy, acquired microcephaly, neurological impairment, and death before age 5 (12 months to 5 years). Patients also had lactic acidosis and urinary excretion of 3-methylglutaconic acid (3MCGA).1, 2 An additional case had renal stones, liver failure, and progressive neurological decline with death at 22 months.3 We discuss 7 unreported patients.

Clinical History

Patients 1 and 2 were monozygotic twin sisters who presented with fulminant liver failure at 3 months (Table 1). Electron microscopy (EM) demonstrated unusual cristae configurations in hepatocytes and Kupffer cells, but subtle abnormalities in skeletal muscle mitochondria initially interpreted as normal (Fig. 1). Their mild neurological findings were attributed to liver disease, so they were listed for transplant but died of liver failure. A younger sister (patient 3) had elevated liver function studies at birth. At 9 months, her liver disease was stable. She died at 13 months. Patient 4 had neonatal onset of transient liver disease with death at 10 months from acute respiratory distress syndrome (ARDS). His older sister (patient 5) exhibited a similar course. Liver histology showed enlarged mitochondria (Fig. 1). A sister of the father (patient 6) had a similar course 24 years earlier. Patient 7 had neonatal onset of transient liver failure. She had bouts of liver disease with severe diarrhea and neurological deterioration and died at age 3 in the course of acute liver disease with vomiting and seizures.

Discussion

Extrahepatic manifestation of QIL1 hepato-encephalopathy varies, but all 7 patients had liver disease with acute liver failure (ALF) in all but 2 patients (5 and 6). In patients 1 and 2, ALF initially appeared to be isolated prompting evaluation for liver transplantation. However, given the high rate of neurological deterioration, mitochondrial hepatopathy attributed to QIL1 ought to be a contraindication for transplantation. Whereas liver disease was the entry point in all patients, its characteristics and severity varied even within the same family. Patients 3, 4, and 7 exhibited neonatal-onset ALF. At presentation, cholestatic jaundice was present in all but 1 patient (patient 5), and gamma-glutamyl transferase (GGT) was normal in 4 patients (1, 2, 5, and 7) and elevated in the other 3. Ammonia was normal or mildly elevated. Lactic acid ranged from 2.7 to 8.6 mmol/L. All patients exhibited urinary excretion of 3MCGA. Therefore, a consistent QIL1 clinical scenario is of early onset and recurrent liver disease of variable severity, most often with cholestatic jaundice and elevated or normal GGT. In that setting, subsequent extrahepatic findings (neurological disease, optic atrophy, and ARDS) and 3MCGA are highly suggestive of QIL1.

For patients 1 and 2, anesthesia exposure likely contributed to their decline given that their sister survived 13 months without anesthesia. ARDS was striking (patients 4 and 5), along with respiratory failure in the literature.3 This may reflect poor brainstem function with aspiration or be part of the QIL1 phenotype given that QIL1 is expressed in lung tissue.4

Characteristic findings on liver EM helps to differentiate this condition. The stacking dysmorphia of the mitochondrial cristae may allow one to distinguish QIL1-related pathology from other metabolic or mitochondrial (mitochondrial DNA depletion syndromes) conditions. However, EM findings vary in different cell types and can be subtle. Although it is not always routine to attain biopsies, multiple images of muscle and liver tissue should be evaluated when attained.

Ultimately, whole-exome sequencing or next-generation sequencing mitochondrial panel (patients 4-6) identified the causative variants in all three families. Because there are only 5 reported cases, QIL1 is not yet on infantile liver failure gene panels. Based on the clinical and management implications of an early diagnosis, we propose that the evaluation of an infant with ALF should include broader genetic testing, especially in the setting of transplant evaluation.