An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated ...proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/β-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.3099C>G; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.
Mevalonate kinase deficiency (MKD) is a severe autoinflammatory disease caused by recessive mutations in MVK resulting in reduced function of the enzyme mevalonate kinase, involved in the ...cholesterol/isoprenoid pathway. MKD presents with periodic episodes of severe systemic inflammation, poor quality of life, and life-threatening sequelae if inadequately treated. We report the case of a 12-year-old girl with MKD and severe autoinflammation that was resistant to IL-1 and TNF-α blockade. In view of this, she commenced intravenous tocilizumab (8 mg/kg every 2 weeks), a humanised monoclonal antibody targeting the IL-6 receptor (IL-6R) that binds to membrane and soluble IL-6R, inhibiting IL-6-mediated signaling. She reported immediate cessation of fever and marked improvement in her energy levels following the first infusion; after the fifth dose, she was in complete clinical and serological remission, now sustained for 24 months. This is one of the first reported cases of a child with MKD treated successfully with tocilizumab and adds to the very limited experience of this treatment for MKD. IL-6 blockade could therefore be an important addition to the armamentarium for the treatment of this rare monogenic autoinflammatory disease.
Abstract
We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)—PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple ...malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects—adenylosuccinate lyase deficiency and AICA-ribosiduria—the PAICS mutation prevented purinosome formation in the patient’s skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient’s fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.
Background
The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in
SUCLA2
or
SUCLG1
. We report here ...25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.
Patients and results
Of the 71 patients, 50 had
SUCLA2
mutations and 21 had
SUCLG1
mutations. In the newly-reported 20
SUCLA2
patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported
SUCLG1
patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with
SUCLA2
mutations and at birth for
SUCLG1
patients. Median survival was 20 years for
SUCLA2
and 20 months for
SUCLG1
. Notable clinical differences between the two groups were hepatopathy, found in 38 % of
SUCLG1
cases but not in
SUCLA2
cases, and hypertrophic cardiomyopathy which was not reported in
SUCLA2
patients, but documented in 14 % of cases with
SUCLG1
mutations. Long survival, to age 20 years or older, was reported in 12 % of
SUCLA2
and in 10 % of
SUCLG1
patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of
SUCLA2
and 80 % of
SUCLG1
patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found.
Conclusions
To our knowledge, this is the largest study of patients with
SUCLA2
and
SUCLG1
deficiency. The most important findings were a significantly longer survival in patients with
SUCLA2
mutations compared to
SUCLG1
mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with
SUCLG1
mutations, whereas epilepsy was much more frequent in patients with
SUCLA2
mutations compared to patients with
SUCLG1
mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire
SUCLA2
gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known
SUCLA2
founder mutation in the Faroe Islands.
Aim: The aim of the study was to identify the genetic background for Aicardi–Goutieres syndrome (AGS) in the Faroe Islands.
Methods: Four patients with AGS were identified. The patients had a ...variable phenotype, from a severe prenatal form with intrauterine foetal death to a milder phenotype, albeit still with an early onset, within the first 2–3 months.
Results: A genome‐wide search for homozygosity revealed one single 15.6 Mb region of homozygosity on chromosome 13, which included RNASEH2B, where a splice site mutation c.322‐3C>G was identified. Screening of 170 anonymous Faroese controls revealed a carrier frequency of approximately 1.8%, corresponding to an incidence of AGS in the Faroe Islands of around 1 in 12 300.
Conclusion: The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harbouring at least one missense mutation. The severe phenotype of the Faroese patients compared with the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal, RNASEH2B proteins, and hence some residual activity of RNASEH2B, explaining their milder phenotype.
Patients with SUCLA2 gene defects characteristically develop the trias of early hypotonia, progressive dystonia and sensori-neural deafness. We describe the clinical course and biochemical phenotype ...in 16 children from the Faroe Islands with a homozygous SUCLA2 splice site mutation. Elevated urinary 3-hydroxyisovaleric acid is a novel biochemical feature in patients. Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia. Direct SUCLA2 sequence analysis is suggested instead of an invasive muscle biopsy to obtain the diagnosis. Nutritional intervention may be considered in SUCLA2 patients.
Perinatal deaths in the Faroe Islands during 1986-95 JOENSEN, FRÓĐI; OLSEN, SJÚRĐUR FRÓĐI; HOLM, TURIĐ ...
Acta obstetricia et gynecologica Scandinavica,
October 2000, Letnik:
79, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Objective. To examine causes of perinatal mortality in the Faroe Islands, where it has been increased compared to other Nordic societies.
Method. Cases were classified according to a fetal/obstetric, ...a fetal/neonatal, and a fetal/obstetric/neonatal classification (classifications C1, C2, and C3, respectively).
Setting. The Faroe Islands 1986–1995; as reference materials were used a) the preceding decade in the Faroes and b) a parallel period in Denmark.
Subjects. We examined all available information regarding each case from hospital records, midwife records, birth certificates, death certificates and autopsy records.
Results. The perinatal mortality was 10.3 per 1,000 total births (83/8,096) compared with 13.7 (102/7,458) in the preceding decade; the fall could be attributed to fewer cases with preeclampsia, antepartum bleedings (C1) and antepartum asphyxia (C2) and the number fell despite an increased occurrence of cases attributed to congenital malformations. Perinatal mortality in Denmark was 8.3 (4,574/550,971), where rates were lower of cases with congenital malformations and fetoplacental dysfunction, but where the rate was higher of cases related to preterm birth (C3).
Conclusions. Although the perinatal mortality rate still is higher in the Faroes than Denmark, the rate had fallen in the Faroes from 1976–85 to 1986–1995. The fall was mainly due to fewer cases attributable to antepartum asphyxia, preeclampsia, antepartum bleedings, and hyaline membrane disease, a pattern compatible with a more efficient perinatal service in the Faroes in the latter period.
The Faeroe Islands has a high incidence of glycogen storage disease type III A, carnitine transporter deficiency and holocarboxylase synthetase deficiency. In the article the incidence, symptoms and ...gene mutations for these three inborn errors of metabolism are reviewed both in general and in specific for children in the Faeroe Islands. None of the mutations for the three diseases is particularly frequent, but all children in the Faeroe Islands with one of the three metabolic diseases are homozygous for one specific mutation, which must be due to a founder effect.
Objective. To examine causes of perinatal mortality in the Faroe Islands, where it has been increased compared to other Nordic societies.
Method. Cases were classified according to a fetal/obstetric, ...a fetal/neonatal, and a fetal/obstetric/neonatal classification (classifications C1, C2, and C3, respectively).
Setting. The Faroe Islands 1986-1995; as reference materials were used a) the preceding decade in the Faroes and b) a parallel period in Denmark.
Subjects. We examined all available information regarding each case from hospital records, midwife records, birth certificates, death certificates and autopsy records.
Results. The perinatal mortality was 10.3 per 1,000 total births (83/8,096) compared with 13.7 (102/7,458) in the preceding decade; the fall could be attributed to fewer cases with preeclampsia, antepartum bleedings (C1) and antepartum asphyxia (C2) and the number fell despite an increased occurrence of cases attributed to congenital malformations. Perinatal mortality in Denmark was 8.3 (4,574/550,971), where rates were lower of cases with congenital malformations and fetoplacental dysfunction, but where the rate was higher of cases related to preterm birth (C3).
Conclusions. Although the perinatal mortality rate still is higher in the Faroes than Denmark, the rate had fallen in the Faroes from 1976-85 to 1986-1995. The fall was mainly due to fewer cases attributable to antepartum asphyxia, preeclampsia, antepartum bleedings, and hyaline membrane disease, a pattern compatible with a more efficient perinatal service in the Faroes in the latter period.
PDF
