Case series
Demographic features of Chinese patients
The mitoC-NET has recorded 850 cases of mitochondrial disease. Among them, 40 cases (4.7%) were clinically diagnosed with mitochondrial leukoencephalopathy, and 36 exhibited pathogenic or likely pathogenic variants in ten genes. IBA57 emerged as the predominant pathogenic gene, accounting for 30.6% cases (11/36). Additional identified genes include NDUFS1, DARS2, NDUFV1, NDUFV2, ISCA1, COX10, GLRX5, SDHAF1, and MT-ND6. Eleven patients (5 males, 6 females) with IBA57 variants, from ten families, were enrolled for the analysis (Fig. 1). According to the OMIM phenotype classification, all were categorized as MMDS3. Maternal prenatal and birth histories were uneventful for all patients. The median age of onset was 0.92 years (range: 0.42–3.50 years, IQR = 1.50 years), and at last contact, all patients were alive (median age 5.25 years, range: 2.08-23.0 years, IQR = 2.67 years, median follow-up time 3.67 years) (Fig. 2a).
Clinical features of Chinese patients
Nine of 11 patients exhibited normal development before initial symptoms. In 2 patients, an infectious triggering factor was recorded, while 6 cases presented with subacute onset. The predominant presenting symptom was developmental regression, accounting for 63.6%, 4 patients got psychomotor regression and 3 presented with motor regression (Fig. 2b). Following the onset, all patients demonstrated a positive pyramid sign, and seven had spastic gaits. Common symptoms included irritable and other emotional problems (N = 7), feeding difficulty (N = 5) and impaired vision (N = 5). Two patients were diagnosed with epilepsy 2.5 and 8 years after the onset, and seizures were effectively controlled with levetiracetam or topiramate (Fig. 2c). Serum lactate was elevated in 66.7% (6/9) patients. Metabolic screening showed a normal range of metabolites, including glycine (N = 6). Cranial MRI revealed symmetrical white matter lesions with cavities in all patients. Lesions were further stratified by discrete location into those affecting the periventricular (N = 10) and deep white matter (N = 8), corpus callosum (N = 8), frontal (N = 8) and parietal lobes (N = 8) (Fig. 2d). Follow-up neuroimaging showed decreased size of lesion and resolved restricted diffusion, with gliosis proliferation in white matter (Fig. 3).
Genetic findings of Chinese patients
All patients underwent whole exon sequencing. Twelve unique variants were identified, including 5 missense variants, 4 frameshift variants (3 deletions and 1 replication), 2 aberrant splicing events and 1 fragment deletion. Ten variants were previously unreported (Fig. 4). The c.286T > C (p.Y96H) variant was detected in 81.8% (9/11) patients. Two patients, case 4 and case 7, harboring the same compound heterozygous variants (p.Y96H and p.H98R), yet showed significantly different clinical symptoms. Case 4 presented with developmental delay and regression, displaying mild spastic gait and the ability to attend kindergarten during convalescent period. In contrast, case 7 experienced severe developmental regression, unable to stand alone at the age of 5, accompanied by vision impairment and epilepsy.
Outcomes at last follow-up
A follow-up ranging from 1.41 to 20 years was conducted on all patients. Rehabilitation training led to significant motor recovery for all patients. At the last contact, parents were asked to subjectively judge their child’s disease course as “improvement”, “stable” or “progression”. Stable clinical conditions were reported in 7 patients, while others showed improvement. The mildest case (P1) presented with encephalopathy characterized by post-infection somnolence and irritability, returning to baseline two weeks after onset. Among the remaining 10 cases, impaired motor function was the major symptoms, while 4 experiencing quadriparesis (Fig. 2e). A median mRS of 3 (range:0–4) was recorded per patient (Fig. 2c). Four out of 7 patients were enrolled in regular schools.
Literature review
A total of 72 cases from 51 families harboring IBA57 variants have been reported. After excluding incomplete and duplicated data, clinical and genetic information was available for 50 patients (35 with MMDS3 and 15 with SP74)[3, 5, 7–23]. Including our cases, a total of 61 patients were finally enrolled for statistical analysis (Fig. 1).
Demographic features of 46 patients with MMDS3
Across the 46 patients (19 male, 26 female and 1 undisclosed gender), 35 were identified through literature review, and 11 were reported by us. The majority of patients (35/46) were of Asian origin, with 58.7% specifically identified as Chinese. Only 11 cases were reported from other continents (Fig. 5a). The median age of onset for all patients was 0.71 years (range: postnatal-3.5 years, IQR = 0.60 years), with Asian patients displaying a later onset (P = 0.001, Fig. 5b). Twelve patients deceased, with a median age at 0.23 years (range: 15 minutes after birth-2.25 years, IQR = 1.29 years) (Fig. 5c). Notably, Chinese patients showed significantly lower mortality rates than the non-Chinese group (2/27 vs 10/19, P = 0.002, Fig. 5d). The survival rate was over 90% in Chinese population at 5 years, indicating a relatively stable living status. However, more than 50% of non-Chinese patients passed away before 3 years of old (P = 6×10− 4, Fig. 5e).
Clinical features of patients with MMDS3
The 46 cases were classified into 3 subtypes: neonatal subtype (< 1 month, N = 7), infant subtype (1 month-1 year, N = 24), and childhood subtype (> 1 year, N = 15). Individuals of Chinese descent predominantly presented as infant and childhood subtypes, whereas those of non-Chinese origin were more likely to exhibit with infant and neonatal subtypes (Fig. 6a).
Neonatal subtype: Among the 7 cases, one was from China. Intrauterine growth restriction was observed in four cases, and three had low Apgar scores at birth. Hypotonia (7/7) and respiratory distress (6/7) shortly after birth were the most common initial symptoms. Elevated blood lactate levels were prevalent (6/6), along with increased glycine levels (3/3) and reduced activity of respiratory chain complexes (4/4) (Table 1). Cranial MRI in four cases revealed white matter and brainstem lesions, polymicrogyria, and ventricular dilatation. All cases died of respiratory failure within the first three months of life (Fig. 6b and 6c).
Table 1
Clinical features of patients present with MMDS3 (n = 46)
Subtypes | Neonatal subtype (n = 7) (%) | Infant subtype (n = 24) (%) | Childhood subtype (n = 15) (%) |
Our cohort: Published cases | 0:7 | 6:18 | 5:10 |
Chinese: Non-Chinese | 1:6 | 16:8 | 10:5 |
Perinatal abnormality | 4/7 (57.1) | 0/24 | 0/15 |
Ttriggers of onset | 2/6 (33.3) | 6/19 (31.6) | 8/13 (61.5) |
Normal development before onset | NA | 16/22 (72.7) | 9/12 (75.0) |
Symptoms of onset | | | |
Hypotonia | 7/7 (100.0) | 0/24 | 0/15 |
Respiratory distress | 6/7 (85.7) | 0/24 | 0/15 |
Developmental regression | NA | 22/24 (91.7) | 12/15 (80.0) |
Developmental delay | NA | 2/24 (8.3) | 1/15 (6.7) |
Visual impairment | NA | 0/24 | 1/15 (6.7) |
Encephalopathy | NA | 0/24 | 1/15 (6.7) |
Main clinical symptoms | | | |
Respiratory distress | 7/7 (100.0) | 0/24 | 0/15 |
Impaired motor function | 2/2 (100.0) | 12/12 (100.0) | 10/11 (90.9) |
Positive pyramidal signs | NA | 15/15 (100.0) | 10/15 (66.7) |
Dysphagia | 2/2 (100.0) | 7/11 (63.6) | 4/7 (57.1) |
Seizures | 0/7 | 7/20 (35.0) | 5/11 (45.5) |
Visual impairment | NA | 4/12 (33.3) | 4/7 (57.1) |
Laboratory test | | | |
Increased serum lactate | 6/6 (100.0) | 9/22 (40.9) | 6/10 (60.0) |
Increased serum glycine | 3/3 (100.0) | 3/6 (50.0) | 0/3 |
Brain MRI | | | |
Ventricular dilatation | 2/4 (50.0) | 6/24 (25.0) | 4/15 (26.7) |
White matter | 3/4 (75.0) | 24/24 (100.0) | 15/15 (100.0) |
Periventricular white matter | NA | 20/24 (83.3) | 12/15 (80.0) |
Deep white matter | NA | 16/24 (66.7) | 7/15 (46.7) |
Cavitating leukoencephalopathy | NA | 18/24 (75.0) | 10/15 (66.7) |
Internal capsule | NA | 12/24 (50.0) | 4/15 (26.7) |
Corpus callosum | 1/4 (25.0) | 17/24 (70.8) | 11/15 (73.3) |
Brainstem | 2/4 (50.0) | 7/24 (29.2) | 2/15 (13.3) |
Cerebellum | 0/4 | 7/24 (29.2) | 1/15 (6.7) |
Infant subtype: Among the 24 patients, 16 were of Chinese descent. The pregnancies were uneventful for all patients, with normal pre-onset development observed in 16 cases. Infection and vaccination triggered the onset in 6 out of 19 patients. Developmental regression (22/24, 91.7%) was the predominant initial presenting symptom, primarily characterized by motor regression (59.1%). Summative analysis of the clinical features revealed the most common clinical manifestations to be impaired motor function after onset (12/12), positive pyramidal signs (15/15), and dysphagia (7/11). Seizures occurred in seven patients, effectively controlled with antiepileptic medications. Elevated blood lactate was observed in only 40.9% (9/22) of cases, while 50% (3/6) showed increased serum glycine levels. Among the seven patients with reduced mitochondrial respiratory chain complex activity, concurrent reductions were noted in LIAS, PDHc, α-KGDH and BCKDH activities. White matter lesions were universal, primarily in periventricular white matter, deep white matter, and internal capsule regions; cavities were present in 75.0% (18/24) of cases. Additionally, the corpus callosum (17/24), brainstem (7/24), and cerebellum (7/24) were affected, with no basal ganglia involvement (Table 1). Four patients passed away at last report. Survival analysis demonstrated a survival rate of over 75% at 5 years (Fig. 6b and 6c).
Childhood subtype: Ten of 15 childhood patients were Chinese. Development was normal in 9 cases, and 8 had a history of infectious experiences before onset. 80.0% of patients initially manifested with developmental regression, characterized by impaired motor function, positive pyramidal signs, and dysphagia as the key clinical symptoms. Visual impairment was more prevalent in childhood subtype (57.1%). Elevated blood lactate was observed in 6 patients (60.0%), while blood glycine levels were normal. All patients showed white matter involvement, with 66.7% (10/15) exhibiting cavitating lesions, and 73.3% (11/15) involving corpus callosum, however the basal ganglia remained unaffected (Table 1). With 1 patient deceased and 1 not documented, the remaining 13 survivors displayed stable conditions. The survival rate was up to 90% at 5 years compared to other subtypes (P < 1×10− 4, Fig. 6b and 6c).
Genetic findings of patients with MMDS3
A total of 44 variant loci were identified, including 27 missense variants, 8 frameshift variants, 6 nonsense variants, 2 aberrant splicing events, and 1 large segment deletion (Fig. 3). The c.286T > C variant was the most common in Chinese population, accounting for 85.2% (23/27) of cases. Three cases carrying the p.G104C and two cases with the p.Q314P variants were all of the neonatal subtype. However, no specific correlation was observed between genotypes and phenotypes.
The clinical and genetic findings of patients with SP74
Fifteen cases (11 males, 4 females) from three families were recorded, of which two were Chinese. The median age of onset was 6 years (range: 1 year-12 years, IQR = 7 years), with 80% of patients (N = 12) presenting after 3 years of age. All patients exhibited normal development prior to onset and were alive at last contact (median age 25 years, range: 5 years-65 years, IQR = 21 years). Common clinical manifestations included spastic paraplegia (14/15), visual impairment (10/13), and peripheral neuropathy (9/13). A total of five variants were identified, comprising 2 missense, 1 nonsense, 1 synonymous and 1 duplication. The p.R8X variant had been previously reported in 2 patients with the infant MMDS3 subtype.