Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

INTRODUCTION: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study.

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984-86, HUNT2 1995-97, HUNT3 2006-08 and HUNT4 2017-19. The study sample was aged 70-102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer's disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs.

Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations.

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.

Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts.

Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease.

INTRODUCTION: Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. METHODS: Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. RESULTS: Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) - 7, POLG - 7, SURF1 - 10, PDHc deficiency - 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. CONCLUSIONS: This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease.

TRNT1 deficiency: clinical, biochemical and molecular genetic features.

BACKGROUND: TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). RESULTS: We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3' CCA addition to mitochondrial tRNAs (tRNA(Cys), tRNA(LeuUUR) and tRNA(His)) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile. CONCLUSIONS: Our report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.

Treatable Leigh-like encephalopathy presenting in adolescence.

Wernicke's encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency. A rare genetic defect of thiamine transporter-2 may lead to similar clinical features, biotin-thiamine responsive basal ganglia disease (BTBGD). A 15-year-old girl developed rapid onset ptosis and ophthalmoplegia evolving into a subacute encephalopathy. Neuroimaging demonstrated symmetrical basal ganglia and mid-brain lesions reminiscent of Leigh's subacute necrotising encephalomyelopathy. Oral biotin and thiamine were started, and symptoms improved dramatically the next day. The therapeutic response suggested SLC19A3, encoding thiamine transporter-2, as a strong candidate gene and Sanger sequencing revealed a novel homozygous c.517A>G;p.Asn173Asp mutation, which segregated with disease within the family. BTBGD is a potentially treatable neurological disorder and should be considered in the differential diagnosis of Leigh syndrome and Wernicke's encephalopathy. Since delayed treatment results in permanent neurological dysfunction or death, prompt diagnosis and early initiation of biotin and thiamine therapy are essential.

A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.

Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown.

SURF1 deficiency: a multi-centre natural history study.

BACKGROUND: SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency. METHODS: We conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS and nuclear-encoded complex I-deficient LS patients were obtained from previous publications. The survival of SURF1-deficient patients was compared with these two groups using Kaplan-Meier survival analysis and logrank test. RESULTS: The majority of patients (32/44, 73%) presented in infancy (median 9.5 months). Frequent symptoms were poor weight gain (95%, median age 10 months), hypotonia (93%, median age 14 months), poor feeding/vomiting (89%, median age 10 months), developmental delay (88%, median age 14 months), developmental regression (71%, median age 19 months), movement disorder (52%, median age 24 months), oculomotor involvement (52%, median age 29 months) and central respiratory failure (78%, median age 31 months). Hypertrichosis (41%), optic atrophy (23%), encephalopathy (20%), seizures (14%) and cardiomyopathy (2%) were observed less frequently. CONCLUSIONS: SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.

NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.

The molecular basis of cytochrome c oxidase (COX, complex IV) deficiency remains genetically undetermined in many cases. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous pedigree with isolated COX deficiency linked to a Leigh syndrome neurological phenotype. Unexpectedly, affected individuals harbored homozygous splice donor site mutations in NDUFA4, a gene previously assigned to encode a mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase) subunit. Western blot analysis of denaturing gels and immunocytochemistry revealed undetectable steady-state NDUFA4 protein levels, indicating that the mutation causes a loss-of-function effect in the homozygous state. Analysis of one- and two-dimensional blue-native polyacrylamide gels confirmed an interaction between NDUFA4 and the COX enzyme complex in control muscle, whereas the COX enzyme complex without NDUFA4 was detectable with no abnormal subassemblies in patient muscle. These observations support recent work in cell lines suggesting that NDUFA4 is an additional COX subunit and demonstrate that NDUFA4 mutations cause human disease. Our findings support reassignment of the NDUFA4 protein to complex IV and suggest that patients with unexplained COX deficiency should be screened for NDUFA4 mutations.

Pregnancy and its management in women with GSD type III - a single centre experience.

We present a review of our experience and pregnancy outcome in patients with GSD III managed by our centre. Between 1997 and 2010 there were 15 pregnancies in seven women with GSD III. Four women had GSD IIIb (nine pregnancies) and three GSD IIIa (six pregnancies). There was a successful outcome in all 15 pregnancies with delivery of 15 liveborn infants. Four infants were of low birthweight (<2nd centile) but all have developed normally apart from one with behavioural/psychiatric problems. Three women had pre-existing cardiomyopathy prior to pregnancy. One of these women had deterioration of her cardiomyopathy during pregnancy and again in the post-partum period. Women with GSD III do not seem to have any issues with fertility. Overall the outcome of pregnancy for both mother and child is good. Care needs to be taken to avoid maternal hypoglycemia which may be associated with intrauterine growth restriction and low birth weight. Cardiac function should be monitored carefully particularly in those with pre-existing cardiomyopathy.

The clinical utility of two renin mass methods to detect primary hyperaldosteronism compared with renin activity.

BACKGROUND: Primary hyperaldosteronism (PHA) is characterized by a raised plasma aldosterone concentration (PAC) with suppressed plasma renin activity (PRA). We evaluated two renin mass methods for PHA detection compared with the PAC:PRA ratio. METHODS: Samples from patients attending a specialist hypertensive clinic were analysed by Liaison automated chemiluminescent immunoassay and Diagnostic Systems Laboratories (DSL) immunoradiometric assay (IRMA) for renin mass; I(-125) radioimmunoassay of angiotensin I generated from endogenous angiotensinogen for PRA; Siemens Coat-a-count radioimmunoassay for PAC. Subjects included those on ß-blockers which suppress renin, causing an equivalent biochemical picture to PHA. Aldosterone/renin ratios (ARR) were calculated for PRA, DSL and Liaison methods. The first 100 subjects were used to identify cut-off ratios ensuring maximum specificity at 100% sensitivity for PHA detection. This cut-off was retested in a subsequent population (n = 43). RESULTS: A Liaison renin of 5 ng/L separated PRAs of ≤0.5 from ≥0.6 pmol/mL/h. The DSL method had greater scatter. In population 1 (18 PHA), cut-off ratios of >118 pmol/ng (Liaison) and >60 pmol/ng (DSL) gave specificities of 58.5% and 61%, respectively, with 100% sensitivity. If criteria for PHA included PAC ≥350 pmol/L and excluded ß-blocked subjects, specificity increased to 95.1% and 90% for Liaison and DSL, respectively. In population 2 (6 PHA), specificities for Liaison and DSL ARRs were 86.4% and 78.3%. Using the ratio with PAC and ß-blocker criteria, specificities for Liaison and DSL were 97.3% and 86.5%, respectively. CONCLUSIONS: The Liaison ARR used with PAC and ß-blocker criteria provided an automatable alternative to identify the same patients as the PAC:PRA ratio.