Rare Genetic Cause Research Articles

Genetic Causes of Rickets.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child.

Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity.

Hypoparathyroidism and recurrent hypomagnesaemia since infancy: a rare genetic cause

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

P.369 - Multi-system disorder and severe recurrent rhabdomyolysis due to TANGO2 mutations in a 3 year-old child

Recessive mutations in TANGO2 result in a rare genetic cause of severe recurrent rhabdomyolysis (RM) associated with encephalopathy and cardiomyopathy. A 3-year-old boy was referred for genetic investigations following two extremely severe RM episodes requiring intensive care unit admissions. The first episode occurred at 13 months most probably triggered by a throat infection and dehydration (CK increase: Day 1: 1,400 IU/L, Day 1 (night): 103,000 IU/L, Day 2: 177,000 IU/L and Day 3: 210,000 IU/L). He received treatment for mild hypothyroidism and steroids on Day 4. Complications included hyponatraemia with comatose state, nosocomial bacterial infection and heart failure. In the period between the first and the second hospitalization, he slowly regained muscle tone and started crawling at 18 months of age. The second RM episode occurred at 27 months following a viral infection, serum CK peaked at 225,000 IU/L, decreasing over 4 weeks (147 IU/L). Previous medical history included psychomotor delay. Brain MRI showed moderate enlargement of ventricles and bilateral frontotemporal subarachnoid spaces, mild hypomyelination and reduced thickness of the corpus callosum. Normal investigations included respiratory chain enzymes in muscle tissue, urine organic acids, acylcarnitine profile, urine and plasma amino acidogram and s-Ab anti myositis specific (immunblotting). WES confirmed compound heterozygous mutations in TANGO2 in the proband and in his asymptomatic sister (16 months), which were inherited from both parents (nonsense p.Arg88*, p.Glu112fs frameshift). Following the genetic diagnosis, the patient has been regularly monitored by a multidisciplinary team. The compound heterozygous TANGO2 mutations point to a virtually complete functional knock-out of the TANGO2 protein in the proband. Looking for recessive mutations in TANGO2 should be considered in young children presenting with a combination of psychomotor delay, hypothyroidism, cardiomyopathy and RM.

Phelan-McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports.

The heterogeneity of patient phenotype data are an impediment to the research into the origins and progression of neuropsychiatric disorders. This difficulty is compounded in the case of rare disorders such as Phelan‐McDermid Syndrome (PMS) by the paucity of patient clinical data. PMS is a rare syndromic genetic cause of autism and intellectual deficiency. In this paper, we describe the Phelan‐McDermid Syndrome Data Network (PMS_DN), a platform that facilitates research into phenotype–genotype correlation and progression of PMS by: a) integrating knowledge of patient phenotypes extracted from Patient Reported Outcomes (PRO) data and clinical notes—two heterogeneous, underutilized sources of knowledge about patient phenotypes—with curated genetic information from the same patient cohort and b) making this integrated knowledge, along with a suite of statistical tools, available free of charge to authorized investigators on a Web portal https://pmsdn.hms.harvard.edu. PMS_DN is a Patient Centric Outcomes Research Initiative (PCORI) where patients and their families are involved in all aspects of the management of patient data in driving research into PMS. To foster collaborative research, PMS_DN also makes patient aggregates from this knowledge available to authorized investigators using distributed research networks such as the PCORnet PopMedNet. PMS_DN is hosted on a scalable cloud based environment and complies with all patient data privacy regulations. As of October 31, 2016, PMS_DN integrates high‐quality knowledge extracted from the clinical notes of 112 patients and curated genetic reports of 176 patients with preprocessed PRO data from 415 patients.

Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders

Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology.

Role of Niemann-Pick Type C Disease Mutations in Dementia.

Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.

Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

A familial adrenal incidentaloma story

Primary macronodular bilateral adrenal hyperplasia (PMBAH) was incidentally identified in a 69-year-old woman who developed a biliary colic. She had a 30-year history of hypertension and was treated by three antihypertensive drugs. Concomitantly, one of her four sons was also referred after incidentally discover of a PMBAH. This 50-year-old man had developed, 1 year before, severe hypertension needing four antihypertensive drugs. Moreover, 2 years before, another son was also incidentally diagnosed for PMBAH through an ampulloma cure. This 49-year-old man had no hypertension but osteoporosis treated for many years. Hormonal evaluation showed in all three patients: basal suppressed ACTH, no plasma cortisol suppression after 1-mg over-night dexamethasone suppression test and aberrant adrenal sensitivity in response to several ligands (all data will be shown on poster). The mother underwent surgical resection of the biliary duct tumor. Histopathology is compatible with a neuroendocrine tumor. Immunostainings and genetic testing are still in progress. PBMAH is often genetically determined and several genes have been identified, ARMC5 being the last one. Illegitimate receptor expression is observed in the majority of PBMAH. However, the associated-tumors phenotype exhibited by this family does not enter into the spectrum of the described malignancies predisposing syndromes (no hyperparathyroidism). Anyway, investigations are continued in the others children and grandchildren. This case illustrates the phenotype variability within one family with a rare genetic cause of Cushing's syndrome and highlights the importance of a complete clinical characterization to permit phenotype-genotype correlations for a better knowledge of this disease.

Prevalence and impact of co-morbidity in COPD due to Alpha 1 Antitrypsin deficiency

<p><strong>Background</strong></p><p>Alpha 1 antitrypsin deficiency (AATD) is a rare genetic cause of chronic obstructive pulmonary disease (COPD). There are a number of conditions which are recognized to be common as co-morbidities in COPD unrelated to AATD, and a co-morbidity specific prognostic score exists (COTE index). In this manuscript we sought to describe the COPD related, and unrelated, co-morbidities seen in AATD and assess their impact on outcome. The relevant literature is also reviewed.</p><p><strong>Methods</strong></p><p>All PiZZ AATD patients who have COPD from the UK AATD registry were selected, and graded for severity of COPD using the GOLD criteria. Medical notes were reviewed to ascertain co-morbidity, and used to calculate the COTE score. Each co-morbid condition was tested for association with GOLD stage and subsequent death. Multivariate analyses, adjusting for smoking, age and GOLD stage, were used to ascertain independent relationships to death. COTE score was compared between GOLD groups and between survivors and those that died. Selected co-morbid diseases were also assessed using multivariate analyses for their relation to lung function decline.</p><p><strong>Results</strong></p><p>The most common co-morbid disease in AATD was bronchiectasis (31.1% of patients). Some common COPD related conditions were seen, such as osteoporosis (11.9%). Liver disease was observed in 5.5% of patients. In univariate analyses the presence of osteoporosis, depression or gastro-oesophageal reflux (GORD) associated with GOLD stage, being more common in group D patients (all p<0.05). No co-morbid disease was associated with death after adjustment for co-variates. COTE scores were generally low and did not differ between survivors and those that died.</p><p><strong>Conclusion</strong></p><p>Co-morbid disease is common in AATD, but differs from usual COPD, and has little impact on mortality and lung function decline. The COTE index is not valid for use in AATD.</p>

Blepharophimosis ptosis epicanthus inversus syndrome (BPES): A rare cause of primary ovarian insufficiency

Introduction: Most common cause of primary ovarian insufficiency is idiopathic (80–90%). Other causes are chromosomal, genetic, autoimmune, metabolic, infectious, and iatrogenic. blepharophimosis ptosis epicanthusinversus syndrome (bPEs) is a rare genetic cause of primary ovarian insufficiency. It mainly affects development of eyelids and has autosomal dominant inheritance. the bPEs is of two type, type I and II. both of which include the eyelid malformations and other facial features. type I is associated with primary ovarian insufficiency in women. We studied three cases who presented with bPEs in Gynecology OPD of AIIMs rishikesh over a period of six months.

Normal Variation in Pubertal Timing: Genetic Determinants in Relation to Growth and Adiposity.

In humans, there is a considerable variation in age of onset of puberty. Twin studies have indicated that pubertal timing is a highly heritable trait. Recently, a few rare genetic causes of precocious puberty have been reported as well as genetic mutations associated with isolated hypogonadotropic hypogonadism. Genome-wide association (GWA) studies have helped to explore the genetic determinants of the normal variation in pubertal timing, but have been able to explain only 2.7% of the variance in age at menarche, highlighting the involvement of multiple genes with small effect sizes. These studies indicate an overlap of genes involved in pubertal timing and adiposity, and epidemiological data suggest the existence of a pathway of early infancy weight gain, increased height gain in childhood, earlier pubertal timing and increased adiposity in adulthood. This chapter summarises the data from GWA and epidemiological studies on the normal variation in pubertal timing in relation to growth and adiposity. We discuss putative mechanisms linking early life events to pubertal timing, potential short-term and life-course consequences of earlier pubertal timing, and the impact of these data on clinical management of pubertal disorders.

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers

IntroductionTBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far. MethodsWe describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes. ResultsTwo carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS. DiscussionThis study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.

De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.

The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes.

Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS. Rarer genetic causes of ALS include mutation of optineurin (mt OPTN). Furthermore, optineurin protein has been localized to the ubiquitylated aggregates in several neurodegenerative diseases, including ALS. This study: (i) investigated the frequency of mt OPTN in ALS patients in England; (ii) characterized the clinical and neuropathological features of ALS associated with a mt OPTN; and (iii) investigated optineurin neuropathology in C9ORF72-related ALS (C9ORF72-ALS). We identified a heterozygous p.E322K missense mutation in exon 10 of OPTN in one familial ALS patient who additionally had a C9ORF72 mutation. This patient had bulbar, limb and respiratory disease without cognitive problems. Neuropathology revealed motor neurone loss, trans-activation response DNA protein 43 (TDP-43)-positive neuronal and glial cytoplasmic inclusions together with TDP-43-negative neuronal cytoplasmic inclusions in extra motor regions that are characteristic of C9ORF72-ALS. We have demonstrated that both TDP-43-positive and negative inclusion types had positive staining for optineurin by immunohistochemistry. We went on to show that optineurin was present in TDP-43-negative cytoplasmic extra motor inclusions in C9ORF72-ALS cases that do not carry mt OPTN. We conclude that: (i) OPTN mutations are associated with ALS; (ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient; and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration.

Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear

Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders.

Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism

To clarify the molecular basis of hypogonadotropic hypogonadism (HH). Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation sequencing, followed by in silico functional assessment and messenger RNA/DNA analyses of the mutants/variants. Research institute. Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH. None. Frequency and character of molecular abnormalities. Pathogenic defects were identified in 14 patients with various types of HH, although oligogenicity was not evident in this patient group. As rare abnormalities, we identified a submicroscopic deletion involving FGFR1 and an SOX3 polyalanine deletion in patients with IHH, and a WDR11 splice site mutation in a patient with CPHD. No disease-associated polymorphism was detected in the 58 patients. The present study provides further evidence that mutations and deletions in the known causative genes play a relatively minor role in the etiology of HH and that submicroscopic rearrangements encompassing FGFR1 can lead to IHH as a sole recognizable clinical feature. Furthermore, the results indicate for the first time that polyalanine deletions in SOX3 and mutations in WDR11 constitute rare genetic causes of IHH and CPHD, respectively.

Genetic evaluation of short stature.

Genetics plays a major role in determining an individual's height. Although there are many monogenic disorders that lead to perturbations in growth and result in short stature, there is still no consensus as to the role that genetic diagnostics should play in the evaluation of a child with short stature. A search of PubMed was performed, focusing on the genetic diagnosis of short stature as well as on specific diagnostic subgroups included in this article. Consensus guidelines were reviewed. There are a multitude of rare genetic causes of severe short stature. There is no high-quality evidence to define the optimal approach to the genetic evaluation of short stature. We review genetic etiologies of a number of diagnostic subgroups and propose an algorithm for genetic testing based on these subgroups. Advances in genomic technologies are revolutionizing the diagnostic approach to short stature. Endocrinologists must become facile with the use of genetic testing in order to identify the various monogenic disorders that present with short stature.

Progressive myoclonic epilepsies

To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.