Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity.
encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for ...proper mitochondrial fission. The clinical phenotype of
mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in
(c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in
.
Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an ...aspartate-glutamate carrier located within the inner mitochondrial membrane.
We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70-1)_(212 + 1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months.
As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.
There appears little consensus concerning protein requirements in phenylketonuria (PKU).
A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on ...prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute PS) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics.
The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1year, >2–3g/kg/day; 1–3years of age, >2–3g/kg/day; 4–10years of age, >1.5–2.5g/kg/day) and Southern Europe (n=10 centres) (infants <1year, 2.5g/kg/day, 1–3years of age, 2g/kg/day; 4–10years of age, 1.5–2g/kg/day), than by Eastern Europe (n=4 centres) (infants <1year, 2.5g/kg/day, 1–3years of age, >2–2.5g/kg/day; 4–10years of age, >1.5–2g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1year, >2–2.5g/kg/day, 1–3years of age, 1.5–2g/kg/day; 4–10years of age, 1–1.5g/kg/day). Total protein prescription was similar in patients aged >10years (1–1.5g/kg/day) and maternal patients (1–1.5g/kg/day).
The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.
•In PKU, the total protein prescribed varied widely between European centres.•The amount of total protein appears to be influenced by geographical European region.•North Europe prescribed highest amounts of total protein and least in West Europe.•All PKU centres give in excess of the FAO/WHO/UNU safe levels of protein intake.
Adenosine kinase deficiency (ADK deficiency) is a recently described disorder of methionine and adenosine metabolism resulting in a neurological phenotype with developmental delay, muscular ...hypotonia, and epilepsy as well as variable systemic manifestations. The underlying neuropathology is poorly understood. We have investigated MRI and (1)H-MRS changes in ADK deficiency in order to better understand the in vivo neuropathologic changes of ADK deficiency.
Systematic evaluation of 21 MRIs from eight patients (age range 9 days-14.6 years, mean 3.9 years, median 2.7 years) including diffusion-weighted imaging in six and (1)H-MRS in five patients.
Brain maturation was delayed in the neonatal period and in infancy (6/6), but ultimately complete. White matter changes occurring in five of eight patients were discrete, periventricular, and unspecific (4/5), or diffuse with sparing of optic radiation, corona radiata, and pyramidal tracts (1/5). Choline was low in white matter spectra (3/3), while there was no indication of low creatine in white matter or basal ganglia (5/5), and diffusion was variably decreased or increased. Central tegmental tract hyperintensity was a common finding (6/8), as was supratentorial atrophy (6/8).
MRI changes in ADK deficiency consist of delayed but ultimately completed brain maturation with later onset of mostly unspecific white matter changes and potentially transient central tegmental tract hyperintensity. Immaturity on neonatal MRI is consistent with prenatal onset of disease and reduced choline with lower membrane turnover resulting in delayed myelination and deficient myelin maintenance.
We have used the three-dimensional culture system in alginate beads to redifferentiate human articular chondrocytes which were first expanded on a plastic support. After 15 days in alginate beads, ...electron microscopy showed that cells had synthesized an extracellular matrix containing collagen fibrils. Electrophoretic analysis of proline-labeled cells demonstrated that redifferentiated chondrocytes synthesized mainly type II collagen and its precursors (pro alpha 1II, pc alpha 1II, and pn alpha 1II). After pepsin digestion a small amount of collagen type XI was also detected. These results were confirmed by Northern blot analysis of total RNAs. Hybridization with collagen cDNA probes coding for the alpha 1(II) and alpha 1(I) chains of collagen types II and I showed that chondrocytes cultured in alginate expressed mainly alpha 1(II) mRNA, whereas alpha 1(I) mRNA transcripts were almost undetectable. Such a result was observed even after several passages on plastic flasks, suggesting that dedifferentiated cells were able to revert to a chondrocytic phenotype in this three-dimensional system. However, SV40-transformed chondrocytes were not able to redifferentiate in alginate as no alpha 1(II) mRNAs were detected. Total RNA was converted into cDNA by reverse transcription and amplified by polymerase chain reaction. This technique was employed to amplify mRNAs specific for collagen type II and type X and the large aggregating proteoglycan aggrecan. Two transcripts resulting from an alternative splicing of the complement regulatory protein (CRP)-like domain of aggrecan were originally identified in chondrocytes in monolayers. Like intact cartilage, chondrocytes in alginate expressed only the larger transcript with the CRP domain, whereas the two transcripts were equally expressed in SV40-transformed chondrocytes. Thus, the alginate system appears to represent a relevant model for the redifferentiation of human chondrocytes, especially when only a small cartilage biopsy is available, and could prove useful for pulse-chase studies of patients with skeletal chondrodysplasias. However it was unable to restore the chondrocytic phenotype in virally transformed cells.
Mitochondrial NADH: ubiquinone oxidoreductase (complex I) deficiency accounts for most defects in mitochondrial oxidative phosphorylation. Pathogenic mutations have been described in all 7 ...mitochondrial and 12 of the 38 nuclear encoded subunits as well as in assembly factors by interfering with the building of the mature enzyme complex within the inner mitochondrial membrane. We now describe a male patient with a novel homozygous stop mutation in the NDUFAF2 gene. The boy presented with severe apnoea and nystagmus. MRI showed brainstem lesions without involvement of basal ganglia and thalamus, plasma lactate was normal or close to normal. He died after a fulminate course within 2 months after the first crisis. Neuropathology verified Leigh disease. We give a synopsis with other reported patients. Within the clinical spectrum of Leigh disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI. The diagnosis should not be missed in spite of the normal lactate and lack of thalamus and basal ganglia changes on brain MRI.
ECHS1 encodes the short chain enoyl coenzyme A (CoA) hydratase an enzyme located in the inner mitochondrial Matrix, which catalyzes the second step of fatty acid oxidation and is involved in the ...metabolism of valine and isoleucine. Recently two siblings with mutations in ECHS1 have been described presenting a clinical picture with symmetrical basal ganglia alterations and encephalopathy suggesting a mitochondrial disease. This disorder can be diagnosed by increased excretion of S-(2-carboxypropyl) cysteine and methacrylyl-CoA and acryloyl-CoA in urine (Peters et al. Brain 2014 Nov;137:2903–8). Method We report 12 patients from 8 families with mutations in ECHS1 and demonstrate the large phenotypic spectrum of this defect. Results In all patients severe dystonia, mental retardation and deafness were the leading symptoms. In 7/12 epilepsy was described; in 4/12 there was cardiomyopathy. No other inner organs were involved. The beginning of symptoms varies from birth to 3 years of age. The oldest patient is 32 years old. 4/12 died between 4 months and 8 years of age. In 7/12 patients brain MRI revealed symmetrical changes of the basal ganglia and in 3/11 white matter disease. Elevated lactate in blood/CSF was found in 7/12 patients. Only 2/8 patients showed abnormal results in the activity of pyruvate dehydrogenase complex (PDHc) and respiratory chain complexes (RCC)in muscle. Conclusion ECHS1-deficiency is a newly recognized metabolic disorder with a “mitochondrial” phenotype but frequently normal activity of PDHc and RCC. This combination should prompt to investigate S-(2-carboxypropyl)cysteine, methacrylyl-CoA and acryloyl-CoA for early diagnosis. This will be particularly important, if a treatment is available: a diet reduced in valine and isoleucine, the precursors of the potentially toxic metabolites might be a promising approach.
Mutations in Sco2, a protein involved in copper trafficking to the terminal enzyme of the respiratory chain, cytochrome c oxidase, results in infantile hypertrophic cardioencephalomyopathy. We have ...recently shown that copper‐histidine (Cu‐his) supplementation of Sco2‐deficient myoblasts rescues COX activity in vitro. Here, we report a patient with SCO2 mutations and with resolution of severe hypertrophic cardiomyopathy. Weighing up the evidence, the most likely explanation for the improved cardiac function in this patient was the subcutaneous application of Cu‐his.
The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally ...inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case.
Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is highly variable ...in its clinical expression, because of various mutations in the TNSALP gene. In approximately 14% of the patients tested in our laboratory, only one TNSALP gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these two situations is of importance, especially in terms of genetic counseling, but dominance is sometimes difficult to conclusively determine by using familial analysis since expression of the disease may be highly variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease. We report here the study of eight point mutations (G46 V, A99T, S164L, R167 W, R206 W, G232 V, N461I, I473F) found in patients with no other detectable mutation. Three of these mutations, G46 V, S164L, and I473F, have not previously been described. Pedigree and/or serum alkaline phosphatase data suggested possible dominant transmission in families with A99T, R167 W, and G232 V. By means of site-directed mutagenesis, transfections in COS-1 cells, and three-dimensional (3D) modeling, we evaluated the possible dominant effect of these eight mutations. The results showed that four of these mutations (G46 V, A99T, R167 W, and N461I) exhibited a negative dominant effect by inhibiting the enzymatic activity of the heterodimer, whereas the four others did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant effect were clustered in two regions, viz., the active site and an area probably interacting with a region having a particular biological function such as dimerization, tetramerization, or membrane anchoring.
PDF
