244 cases of MATD with relevant clinical information were identified. 132 patients were male, 107 female, and the sex of the remaining 5 patients was not reported. The patient cohort included 32 pairs of siblings, thereof 4 pairs of twins, and two sets of 3 siblings. In one family, father and son were affected. Median age of patients at time of report was 6.0 years (range: neonatal age to 36 years, n = 198). 214 (91.1%, n = 235) patients were alive at the time of report, while 21 (8.9%) patients had died, most of them from their first metabolic decompensation. Age at death ranged from 7 months to 8 years (median = 16 months).
Information on parental consanguinity was available for 183 patients. In one third (61/183) consanguinity was reported with most parents being first cousins. In 122 cases parents were reported to not be related. Of the 213 patients of whom the ethnic or geographic background was known, 36.6% were Caucasian, 20.2% of Vietnamese (mainly Kinh), 13.1% of Turkish, 6.1% of Indian (mainly from Hyderabad), 5.6% of Chinese, 3.8% of Japanese and 2.8% of Tunisian ancestry. All other origins accounted for 3 or less patients each.
Of 205 symptomatic patients age at presentation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). Neonatal presentation (within the first 4 weeks of life) was the exception (n = 7/205; 3.4%). 89 (43.4%) and 73 patients (35.6%) presented beyond the neonatal period in the first and second year of life, respectively. All patients manifested within the first decade, the latest manifestation was reported in an 8-year-old patient . An overview on the age at presentation is given in Fig. 2.
The vast majority of patients presented with acute metabolic decompensations, while only 4 children first displayed chronic neurologic symptoms such as muscular hypotonia, seizures, hyporeflexia or impaired motor skills [7–10]. 28 patients were diagnosed while asymptomatic, either by newborn screening or by family screening due to an affected sibling. Despite the presymptomatic diagnosis, three patients developed a metabolic crisis later during infancy or childhood . Information on the number of metabolic decompensations was available for 221 patients (Fig. 3). Thereof, 198 patients (89.6%) had at least one metabolic crisis, only 73 (33.0%) suffered more than one acute decompensation. 36 patients (16.3%) had 2 decompensations, 26 (11.8%) experienced 3 to 6 decompensations, and in 3 patients (1.4%) more than 9 acute episodes were reported. 23 patients (10.4%) had remained asymptomatic until the age at report.
Acute decompensations were typically characterized by severe metabolic acidosis (pH < 7.0), ketosis and impaired vigilance/coma. 6 patients displayed neurologic symptoms compatible with metabolic stroke. Other laboratory findings included hypo- or hyperglycemia, mild hyperammonemia and elevated activities of transaminases. In some patients secondary carnitine deficiency was detected. Interestingly, one patient who developed his first hypoglycemic crisis without ketosis during her neonatal period and had recurrent nonketotic decompensations during infancy and childhood was found to be severely carnitine deficient . The authors hypothesized that the lack of ketosis might have been caused by suppressed beta-oxidation due to carnitine deficiency. Many patients required intensive care treatment including mechanical ventilation. Hemodialysis or peritoneal dialysis was performed in at least 11 cases. In one individual a long-QT interval was noted during the first acute episode . One other patient suffered a cardiac arrest but could be successfully resuscitated .
Information on the neurologic outcome was given for 204 of the 223 surviving patients. Thereof, 157 (157/204; 77.0%) showed normal psychomotor development without neurologic abnormalities. Further 5 patients (5/204; 2.5%) were reported to be cognitively normal, but displayed neurologic abnormalities including ataxia, hypotonia, choreoathetosis, dystonia and nystagmus. One patient initially showed hypotonia and gross motor developmental delay at the age of 6 months, but later normalized under therapy . One other patient, who displayed ataxia and diplegia at 4 years after adenoidectomy and mumps, had a normal neurological examination and normal intelligence at 7 years . 40 patients (40/204; 19.6%) showed developmental delay, often combined with neurologic symptoms. Only few patients were described as severely disabled, and in most patients with developmental delay mainly the motor development was impaired. In 13 patients (13/204; 6.3%) movement disorders were reported, including dyskinesia, dystonia, choreoathetosis, dysarthria and myoclonic jerks. Seizures were rare in this cohort and only reported in 2 (surviving) patients apart from metabolic decompensations [10, 11].
For 10 of the 21 deceased patients data on neurocognitive development and neurological symptoms are available. Three patients showed developmental delay eventually combined with ataxia, seizures and muscular hypotonia, while seven were reported with normal development until death.
Imaging data (MRI or CT) were available of 71 patients. Brain imaging yielded normal results in 52.1% of patients (37/71) and showed abnormalities in 47.9% (34/71). The most common findings were basal ganglia changes with characteristic T2 hyperintensities affecting mainly the globi pallidi, the putamen, the lentiform and caudate nuclei, but also the substantia nigra. Other findings comprised internal and external capsule lesions, cortical and subcortical atrophy, involvement of the mesencephalon as well as scattered foci in the periventricular and subcortical white matter.
Information on dietary treatment was given for 163 patients. 134 patients (82.2%) followed a specific diet at least transiently. Thereof, 86 patients (86/163; 52.7%) were on either a low isoleucine or low-protein diet. Protein restriction was mostly only mild with a protein uptake up to 2 g/kg/day. In 3 patients a natural aversion against high-protein food resulting in a self-selected protein restriction was mentioned [12–14]. 47 patients (47/163; 28.8%) followed a diet restricted in protein and fat, however, the majority of them (41/47) during metabolic crises only. None of the patients received a special amino acid mixture. One patient who was initially misdiagnosed with glutaric aciduria type 1 was put on a diet low in tryptophan and lysine until the correct diagnosis of MAT deficiency was made . In some cases the diet was relaxed during the clinical course. 29 patients (29/163; 17.8%) never had any dietary restrictions. Avoidance of fasting and a high carbohydrate intake were usually recommended. For 135 patients, data on carnitine treatment was available. 89 patients (89/135; 65.9%) received oral carnitine supplementation at least transiently (usually between 50–200 mg/kg/day), while for 46 patients (46/135; 34.1%) no carnitine supplementation was reported.
Non-neurologic long-term complications seem to be rather rare in this disorder. Some patients showed failure to thrive, which, however, is not unexpected in view of the size of the study cohort. For a single patient with only limited data given, beta-ketothiolase deficiency and fatal cardiomyopathy were purported . Other organ-specific symptoms were not reported. In one female patient a chromosomal abnormality was found in addition to the diagnosis of MATD . Karyotyping was performed in her cultured fibroblasts as a standard procedure in the diagnostic laboratory and revealed in her case a 47, XXX karyotype. Phytohaemagglutinin stimulated lymphocytes from the patient exhibited a mosaic karyotype of 45,X/47,XXX (25%/75%). At the time of the report the patient was 3 years and 9 months old and showed none of the external stigmata of Turner syndrome.
A total of 4 pregnancies in 3 women with MATD have been reported [13, 18, 19]. All were uncomplicated and resulted in healthy offspring. In one mother, Caesarean section was necessary due to fetal bradycardia.
Enzyme activity studies were performed in 105 patients. They consistently confirmed decreased or absent MAT activity in fibroblasts, lymphocytes or, EBV-transformed lymphoblastoid cells.
Results of ACAT1 mutation analysis were reported for 164 of the 244 patients. 85 patients (85/164; 51.8%) were found to be homozygous for ACAT1 mutations, and in 78 patients (78/164; 47.6%) compound heterozygosity was observed. In one case no details were given, but the disorder was described as “genetically proven”, and in another patient, only one mutation could be identified. Notably, only for 29 of the 67 homozygous patients for whom information on parental consanguinity was available, parents were actually reported to be related. The most common mutation was the ACAT1 c.622C > T, p.(Arg208*) variant, a stop mutation that was found in at least 36 individuals (50% in homozygosity and 50% in compound heterozygosity) of Vietnamese, Dutch and Turkish origin [3, 5]. Thus, it may be a frequent cause of MATD in a wider range of populations. Two other variants that were identified in 12 and 10 patients, respectively, were the splice site variant c.1006-1G > C and the missense mutation c.949G > A, p.(AspD317Asn), that is located at an exonic splice enhancer site and results in exon 10 skipping . All other mutations were described in less than 10 individuals.