We read with interest the article by Shukla et al.1 about two unrelated families in which one member each carried the same ISCA1 mutation manifesting as multiple mitochondrial dysfunction syndrome (MMDS). Comparison with previous investigations was not possible due to missing earlier description of ISCA1 mutations in humans. We have the following comments and concerns.

So far, MMDS was attributed to mutations in the NFU1 (15 patients),2, 3, 4, 5, 6 ISCA2 (6 patients),7 BOLA3 (5 patients)8, 9 and IBA57 (5 patients) genes,10, 11 respectively (Table 1). Altogether, MMDS has been described in 30 patients so far, including the present two.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Irrespective of the underlying mutation, MMDS predominantly manifests as encephalopathy or leukoencephalopathy (Table 1).3 Cerebral manifestations in the 30 patients with MMDS so far reported include absence of head or trunk control, feeding difficulties, lethargy, failure to thrive, psychomotor retardation, neurological regression, spastic quadruparesis, hypotonia, dystonia, tremor, extrapyramidal signs, epilepsy, myoclonus, ataxia, optic atrophy, respiratory insufficiency, muscle hypotonia and cerebral cyst formation (Table 1).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 In addition to leukoencephalopathy, patients carrying NFU1 mutations may present with pulmonary hypertension.2, 5 In patients carrying BOLA3 mutations, optic atrophy, cardiomyopathy, diabetes and diarrhea were additionally reported.8, 9 Patients carrying BOLA3 mutations may present with Leigh syndrome.8 In one patient carrying an IBA57 mutation recurrent vomiting was reported.10 Patient P2 presented with retinopathy.1 Were any other features of MMDS detected in patient P2 and P4?

Table 1 Manifestations of MMDS syndrome
Full size table

From mitochondrial disorders (MIDs) it is well known that they manifest with multiorgan involvement either already at onset of the disease or during progression of the disease (mitochondrial multiorgan disorder syndrome (MIMODS)). Were the two patients prospectively investigated for multisystem disease, particularly for endocrinological, pulmonary, gastrointestinal, renal, bone or dermal involvement? Did any of the two develop MIMODS? Particularly mtDNA depletion syndrome may manifest in organs other than the cerebrum.

Patient P2 had CK elevation.1 Was CK elevation attributed to previous seizure activity, myopathy, cardiomyopathy or macro-CK? Were CK isoenzymes determined?

ISCA2 mutations have been reported to cause mtDNA depletion.7 mtDNA depletion syndromes may manifest as isolated encephalopathy.12 Were the two described patients investigated for mtDNA depletion? Was the amount of mtDNA reduced?

Was pigmentary retinopathy in patient P2 attributed to ISCA1 mutations or due to a double trouble?

Patient P2 is reported to have undergone biochemical investigations.1 What biochemical investigations were carried out? Did patient P2 undergo muscle biopsy and biochemical investigations of the muscle homogenate? Did muscle biopsy show any histological or ultrastructural features of a MID, such as ragged-red fibers, COX-negative fibers, glycogen or fat depositions, SDH-hyperreactive fibers, or abnormally structured mitochondria?

Overall, this interesting case study shows that MMDS refers not only to cerebral abnormalities but also to multiorgan disease, including the eyes, endocrine organs, heart, lungs and the gastrointestinal tract. Although extra-cerebral manifestations may be rare in MMDS, these patients should be actively screened for MIMODS, since some of these manifestations, particularly cardiac involvement, may strongly determine their outcome.