211 cases of HMGCLD were identified and reviewed. 78 patients were female, 101 were male, and the sex of the remaining 32 patients was not reported. The dataset included 8 pairs of siblings, thereof one pair of dizygotic twins. The age at last reported clinical follow-up was provided for 155 patients and ranged from 72 hours to 40 years (median of 48 months). 46 patients were of Turkish origin, 20 Portuguese, 13 Brazilian of Portuguese ancestry, 19 Saudi Arabian, and 12 Spanish. All other origins accounted for 7 or less patients, and of 20 patients no ethnic or geographic origin was reported. Information on parental consanguinity was given in 122 cases with a consanguinity rate of 49% (60/122). 169 (80.1%) patients were alive at the time of report, 34 (16.1%) patients had deceased, and of 8 patients the outcome is not reported. Age at death ranged from 72 hours to 40 years (median 9.5 months, n = 26). Most patients died due to metabolic decompensations, one of them at the age of 24 years during her second pregnancy . One child deceased in his sleep at age 13 months with no apparent previous symptoms. One previously asymptomatic 29-year-old patient died of septic shock with multi-organic failure , one 7 month-old child due to cardiomyopathy and arrhythmias .
Information on the number of metabolic decompensations was available for 171 patients. Thereof, 163 patients (95.3%) suffered at least one metabolic crisis. In 8 patients more than 10 acute episodes were reported. Eight patients never had metabolic decompensations. Two of these patients were diagnosed asymptomatically by family screening [12, 13], three presented with seizures and/or developmental delay [2, 14–16] and two were diagnosed due to hepatomegaly and elevated plasma/serum activities of transaminases [2, 5]. One patient presented with macrocephaly, which was first noted at 2 months, as well as a doll-like facies with frontal bossing and depressed nasal bridge . She also displayed a slight “sun-setting” phenomenon, tendency to opisthotonus and global developmental delay. Although this child never had a metabolic crisis a tendency towards hypoglycemia was reported [17–20]. One patient was diagnosed presymptomatically through family screening, but developed an acute decompensation despite that in the third year of life .
Of 165 patients with acute symptoms the age at presentation was reported (146 cases with exact numbers, and 20 with some information, such as “neonatal onset” or “presentation in the third year of life). Median age at disease onset was 4 months (n = 146). 70/165 (42.4%) patients presented neonatally, 65 (39.4%) and 13 (7.9%) in the first and second year of life, respectively, while the remainder of 17 patients (17/165; 10.8%) showed first symptoms beyond the second year of life only (Figure 1). Within the neonatal onset group 11 patients were already symptomatic on the first day of life. The latest manifestation was reported in a 29-year-old patient who died during the initial metabolic crisis due to multiorgan failure . There was often a significant delay until the correct diagnosis could be made. In one patient it took 36 years between the onset of symptoms and the time of diagnosis [2, 21].
Clinical symptoms of acute decompensations mainly comprised vomiting, lethargy/ coma, tachypnea/apnoea, seizures and moderate hepatomegaly. Few patients presented with stroke-like episodes. Common laboratory findings were (severe) hypoglycemia, metabolic acidosis, elevated activities of transaminases and hyperammonemia. Transaminase activities were often only mildly increased, but episodes of transient elevations up to > 1,000 U/l have been reported in few patients [22, 23]. One child developed an episode of liver dysfunction with massively elevated transaminase activities (AST 4,150 IU/L, ALT 2,200 IU/L) at age 5 months , and another patient showed an AST activity of 11,736 IU/l during a severe metabolic decompensation at age 7 months . Hyperammonemia was rather mild in most cases, however ammonia levels > 1,000 µmol/L have been described, and one patient even presented with severe hyperammonemia of > 2,000 µmol/l requiring peritoneal dialysis .
Information on the neurologic outcome was available of 140 patients (Figure 2). Thereof, 87 (87/139; 62.6%) showed normal psychomotor development without neurologic abnormalities. One 2-year-old patient had trisomy 21  and was therefore not included in the analysis. In 9 patients (9/139; 6.5%) only slight abnormalities were reported including muscular hypotonia or a transiently increased muscle tone, hyperactivity and partial performance weaknesses such as dyslexia anddifficulties in grammar. 44 patients (44/139; 31.7%) showed developmental delay or distinct neurologic abnormalities. 18 patients were described as severely retarded, 6 had a moderate and 4 a mild disability. In 5 cases the degree of neurologic impairment was not further specified. 10 patients showed neurologic symptoms including spastic hemiparesis or tetraplegia, distinct muscular hypotonia, impairment of vision and hearing, cerebellar ataxia, movement disorders, tremor, clonic movements, mild dysarthria, exaggerated deep tendon reflexes and absence of social contact. Seizures were reported in 13 patients (9.0%).
Imaging data (MRI or CT) were available of 60 patients. There will of course be a bias in favour of abnormal findings as imaging is primarily performed in patients with neurologic symptoms. Nevertheless, it is notable that imaging results were unremarkable in only 2 children [2, 26]. The most common findings were white matter changes which were uniformly present in almost all patients. Another frequent observation was cerebral atrophy with dilatation of the ventricular system. Abnormalities reported in few or single patients comprised basal ganglia involvement, demyelinisation, ischemic lesions, chronic subdural hematoma, subdural hygroma and bilateral occipital porencephaly.
In 117 cases information on dietary regimens is available. 9 of these patients (7.7%) had no dietary restrictions, although in one of them a low-leucine diet was recommended. The remaining 108 patients followed a specific diet at least transiently. 46 patients (46/105; 43.8%) were on either a low-leucine (28 patients) or low-protein (18 patients) diet, 57 patients (57/105; 54.3%) followed a diet low in leucine/protein and fat. Only one patient had a fat-restricted diet without protein restriction (1/105; 1%). Few patients had a self-imposed diet already before diagnosis [13, 27–29]. In three cases it was only stated that a diet was performed, but no details were given. Many patients on leucine/ protein restriction received supplementation with a leucine-free amino acid mixture. Some patients received additional carbohydrate supplementation either by corn starch or by glucose polymers. Avoidance of fasting was usually recommended. One patient recieved long-term treatment with diazoxide (25 mg/8 h) . Some patients were supplemented with bicarbonate. In some patients the diet was relaxed at some point during childhood. For 109 patients, data on carnitine treatment was available. In this cohort, carnitine was supplemented in 85 cases (78%), while 24 (22%) patients received no carnitine supplementation.
Apart from neurologic symptoms long-term complications affecting other organs seem to be rather rare. Three patients developed dilated cardiomyopathy with arrhythmias which were fatal in two cases [2, 11, 30], and in one patient left ventricular noncompaction was diagnosed . Two patients were reported with pancreatitis, one 5-year-old girl with a single episode  and one boy with recurrent episodes .
In 4 of 216 cases, HMCGL deficiency was reported in association with another congenital disorder. One patient had a trisomy 21 , one patient was reported with VATERL syndrome , and one patient had a situs inversus totalis and gastroschisis . In the fourth patient who presented with deafness and retinitis pigmentosa an Usher syndrome type I, a rare autosomal recessive condition of profound congenital deafness and severe retinitis pigmentosa associated with developmental delay was suspected .
A total of 8 pregnancies have been reported in 5 women [9, 34–36]. Five pregnancies resulted in healthy offspring, while one mother who already presented with recurrent metabolic decompensations during her first pregnancy died during her second pregnancy at 9 weeks of gestation due to maternal metabolic decompensation . In one patient intrauterine death occurred in the first pregnancy at 10 weeks of gestation during maternal metabolic decompensation, and the second pregnancy was terminated at 6 weeks of gestation in absence of metabolic problems .
Enzymatic studies have been performed in 114 patients confirming a reduced or absent HMGCL activity in leukocytes, Epstein-Barr virus (EBV)-transformed lymphoblastoid cells or fibroblasts in all of them.
Results of HMGCL mutation analysis were reported for 118 patients. Mutations were identified in all 9 exons of HMGCL and also in noncoding regions of the gene. An overview on all mutations identified in the HMCGL gene that were reported in the literature so far is given in Figure 3 (following transcription into the current nomenclature, where required). 86 patients (72.9%) carried homozygous mutations and 24 patients (20.3%) were compound heterozygous for variants in the HMGCL gene. In one of the homozygous patients, paternal uniparental isodisomy of chromosome 1 was confirmed (Aoyama 2015). In 6 patients (5.1%) only one mutation was detected, and in 2 patients (1.7%) no mutation could be identified although HMGCL activity was clearly deficient in fibroblasts [2, 37]. The most common HMGCL mutation was the c.109G>T, p.(Glu37*) variant that was found in a total of 36 patients (30.5%), mostly in homozygosity (homozygous in 28 patients, heterozygous in 8 patients). It was mostly reported in individuals originating from the geographically/ demographically linked countries Brazil, Spain, Portugal and Morocco, but also in two Pakistani patients. The two other common variants that were identified in 12 (10.2%) and 6 patients (5.5%), respectively, were c.122G>A, p.(Arg41Gln) and the splice site mutation c.876+1G>C. While p.(Arg41Gln) was mostly found in individuals from Saudi Arabia, it was also noted in individuals of Turkish and Italian origin. c.876 + 1G > C is common among Turkish patients with HMGCLD. All other mutations were reported in less than 5 individuals.