Classical neonatal forms of the disease
It is the most common form of iMMA. The newborn that was normal after birth becomes unwell few days after and rapidly develops neurological deterioration with lethargy, hypothermia, hypotonia and convulsions, possibly resulting in coma, feeding difficulties, vomiting and dehydration leading to weight loss. Hepatomegaly and hyperammonemic encephalopathy may be present at diagnosis.
Biochemically, the newborn presents with a metabolic acidosis with high anion gap, ketosis, hyperammonemia and hyperglycinemia often associated with cytopenia (neutropenia and/or thrombocytopenia). The initial acute decompensation can lead to multiple organ failure and is life-threatening as any of the recurrent episode.
Late onset forms
These intermediate forms of the disease can occur during the first months or years of life. The main symptoms are vomiting, anorexia, failure to thrive, developmental delay. Patients can present with recurrent episodes of subacute decompensation with digestive and neurologic signs. These episodes are usually triggered by catabolism. Alternatively, patients present with a more insidious chronic form with neurodevelopmental delay.
Over the last decades, advances in clinical care for patients suffering from iMMA have resulted in improved survival however complications can occur.
Acute metabolic decompensations
Despite initiation of treatment, patients are still prone to developing metabolic decompensations throughout life. The predominant trigger for metabolic decompensation is catabolism, which can be induced by an increased energy demand (acute trauma, infection, fever, too much exercise or psychological stress), by reduced energy supply (fasting, vomiting), by a relatively high protein intake (inactivity) or by medication.
Specific organ complications
These also occur despite apparent good metabolic control. The most frequent and devastating in iMMA affect mainly:
- the brain with basal ganglia and white matter lesions possibly responsible for psychomotor retardation, cognitive defects, psychiatric disorders, abnormal movements and epilepsy
- the kidneys with tubulointerstitial nephritis leading to progressive renal failure
- the pancreas with pancreatitis
- the liver with hepatomegaly and liver hyperechogenicity. Rare cases of cirrhosis and even less frequent malignant tumor have been reported
- the eye with optic atrophy
Many of these organ complications have been related to secondary mitochondrial dysfunctions.