Onset Of Symptoms In Adulthood Research Articles

P074 Diagnostic Journeys of Patients with Hypophosphatasia

Abstract Background/Aims Hypophosphatasia (HPP) is an ultra-rare genetic disorder characterised by low activity of tissue non-specific alkaline phosphatase (TNAP). Due to heterogeneity of clinical presentation and lack of definitive biochemical testing, misdiagnosis and diagnostic delay are common. Methods We used information reported by HPP patients to the Rare and Undiagnosed Diseases Study (RUDY) online registry (www.rudystudy.org). We included patients with a self-reported diagnosis of HPP and information on at least one of our outcomes. We described their diagnostic journey, including diagnostic delays, initial symptoms, incorrect diagnoses and healthcare professionals seen. Results 16 participants with a self-reported diagnosis of HPP were included in the analysis with 14/16 female. Of those reporting the date of initial symptom onset, 9/14 participants had symptom onset before the age of 18, whereas five had symptom onset in adulthood. The median time from symptom onset to HPP final diagnosis was 26.5 years (N = 8, IQR 11.2 to 34.6). From the first GP visit related HPP to final diagnosis the median time was 9.5 years (N = 6, IQR 6.2 to 11.1), and from the first hospital visit related to HPP, the median time to final diagnosis was 3.9 years (N = 10, IQR 0.8 to 10.5). Among participants reporting initial symptoms (N = 13), 16 categories of initial symptom were reported, with a median of two initial symptom categories per participant (IQR 1 to 2). The most prevalent initial symptom was pain (10/13, 77%). Of these 10 participants, four had lower limb pain, one had upper limb pain, one had back pain, and five had pain of unspecified location. Skeletal deformity at birth, dental manifestations, joint swelling, and infantile feeding problems were each present in 2/13 participants (15%). Among participants reporting whether they had received other diagnoses prior to that of HPP (N = 13), nine participants (75%) received at least one other diagnosis, with diagnoses of 10 different conditions reported across the cohort. The most common other diagnosis was fibromyalgia (4/13, 31%), followed by hypermobility (2/13, 15%). 21 different types of healthcare professionals were seen prior to final diagnosis. General Practitioners were the most commonly consulted (9/14, 64%). This was followed by allied health professionals (8/14, 57%). Of the eight participants seeing allied health professionals, all eight saw physiotherapists, and 4 (29% of total) also saw at least one other allied health professional. Other types of healthcare professional seen by multiple responders included orthopaedic surgeons (5/14, 36%), rheumatologists (5/14, 36%), geneticists (4/14, 29%), endocrinologists (3/14, 21%), metabolic specialists (3/14, 21%) and dentists (2/14, 14%). Conclusion Patients typically present with a cluster of symptoms, often including pain, and are often seen by general practitioners and physiotherapists before diagnosis. Increasing awareness of HPP in these professions may improve early recognition of the disease. Disclosure D. Marsden: None. R. Ridley: None.

Infectious Diseases and Basal Ganglia Calcifications: A Cross-Sectional Study in Patients with Fahr's Disease and Systematic Review.

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr's disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr's disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis, rubella virus, and Toxoplasma gondii. Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries.

Surgical aspects of classification and neuroimaging characteristics of idiopathic hydrocephalus in adults

Background. Hydrocephalus can be developing by a traumatic brain injury, intracranial hemorrhage, tumor, meningitis of congenital malformation of the central nervous system. When the cause of the hydrocephalus is unclear it is supposed as idiopathic hydrocephalus. The most important classification features are the etiology and level of CSF obstruction. The classification was improved and developed with diagnostic and surgical methods simultaneously. Currently, the neurosurgeons have the possibility for usage of various methods and techniques of surgical treatment with their advantages and disadvantages. Systematization of radiological parameters is necessary to make a decision about the type of the surgery.Aim. To analyze and systematize the neuroimaging characteristics of various forms of idiopathic hydrocephalus in adults, to assess the possible classification of idiopathic hydrocephalus.Materials and methods. Between October 2011 and March 2021 290 patients with idiopathic adult hydrocephalus were operated at the N.N. Burdenko National Medical Research Center of Neurosurgery of the Ministry of Health of Russia: onset of symptoms in adulthood; no indications of the etiology of hydrocephalus and congenital hydrocephalus. The age of the patients was 50 ± 18.2 (18–85) years. The magnetic resonance images of patients were evaluated for the size of the ventricles, condition of convexital and basal subarachnoid spaces, obstruction of the CSF pathways, and changes in the position of the premamillary membrane, septum pellucidum, the roof of the 3rd ventricle and the tonsils of the cerebellum, the size of the sella turcica, the angle of the corpus callosum. The frequency of each of these parameters is statistically estimated for each form of idiopathic hydrocephalus.Results. Aqueduct stenosis has become the most frequent form of idiopathic hydrocephalus. Hydrocephalus in obstruction of the foramen of Monroe, aqueduct, foramen of Magendie, and cisterns of the posterior cranial fossa was significantly more characteristic of young people (p <0.05). Hydrocephalus with obstruction of convexital CSF spaces can be called hydrocephalus of the elderly (p <0.001). Hydrocephalus without verified signs of occlusion CSF pathways occurs equally in all age groups. The FOHR index was significantly more important, and only in case of cisternal obstruction. Enlargement one or both lateral ventricles and flattening of the roof of the 3rd ventricle is characterized for Monro’s foramen obstruction (p <0.001). The membrane at the outlet of the 4th ventricle and the absence of the “flow void” was typically only for patients with obstruction of the foramen of Magendie (p <0.001). Ventral dislocation of the premamillary membrane was characteristic of obstruction of the cerebral aqueduct, the foramen of Magendie, and cisterns of the posterior cranial fossa. Compression of the convexital CSF spaces occurred in case of obstruction of the aqueduct, the foramen of Magendie, but CSF spaces of the posterior cranial fossa – only with obstruction of the foramen of Magendie. Dilation of the 4th ventricle was significantly associated with obstruction of the foramen of Magendie and cisterns of the posterior cranial fossa (p <0.05). DESH symptom was significantly associated with obstruction of convexital CSF spaces (p <0.001). Additional membranes in the cisterns of the posterior fossa were found only in cases of cisternal obstruction (p <0.001). Cerebellar tonsils herniation was observed with obstruction of the foramen of Monroe, cerebral aqueduct, and foramina of Magendie.Conclusion. Because of statistical analysis, general signs found in all types of hydrocephalus, and private ones, characterizing only specific signs of the type of the disease, both were found. The classification is logical and justified, it is well applicable in neurosurgical and radiological practice. It allows rational planning of diagnostic evaluation and treatment of patients. A modern magnetic resonance imaging protocol should include T2 scans (with “flow void”) and FIESTA/CISS scans in the required planes, axial FLAIR scans.

A Familial Cohort of Adult-Onset Alexander Disease (P12-3.016)

<h3>Objective:</h3> To describe a familial cohort of adult-onset Alexander Disease. <h3>Background:</h3> Leukodystrophies are a group of rare, hereditary disorders characterized by abnormal myelination. Each leukodystrophy is caused by abnormalities in one or more genes leading to abnormal production of myelin (hypomyelination) or destruction (demyelination). Leukodystrophies are also classified by the region of the brain or in some cases peripheral nerves that are affected. Alexander Disease is a leukodystrophy characterized by a confluent pattern of demyelination. It is caused by autosomal dominant gain-of-function mutation in the <i>GFAP (glial fibrillary acidic protein)</i> gene. <i>GFAP</i> serves an intermediate filament protein of mature astrocytes; incorrect formation of the protein can lead to astrocyte cytoskeletal collapse and abnormal protein aggregation. Clinically, this can lead to innumerable neurologic manifestations in the affected individual. Alexander Disease predominantly affects neonates, infants, children and rarely adults. We describe a familial cohort of adult-onset Alexander Disease associated with a c.758C&gt;G (p.A253G) mutation of GFAP. This mutation has previously been described in neonates. In this case series we describe the clinical and radiologic features of three sisters with adult-onset symptoms. The first patient is a 53-year-old female who presented with progressive myelopathy and later developed bulbar symptoms. Her 51-year-old sister developed progressive, bilateral leg weakness and gait disturbance. She progressed to have profound cognitive dysfunction. The MRI features include T2 hyperintensities with atrophy in the midbrain and upper cervical spine with peripheral rim brainstem and periventricular garlands. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> These cases describe the clinical and radiologic features of a familial cohort of adult-onset Alexander disease in a mutation previously described only in childhood onset. This also illustrates the importance of considering a diagnosis of Alexander Disease in adult patients and the necessity of genetic analysis of patients and their family members. <b>Disclosure:</b> Dr. Wolf has nothing to disclose. Dr. Gettings has nothing to disclose. Dr. Goodrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono.

Rare Adult-onset Citrullinemia Type 1 in the Postpartum Period: A Case Report.

Citrullinemia type 1 (CTLN1) is a urea cycle disorder caused by defective argininosuccinate synthetase leading to impaired ammonia elimination. Urea cycle disorders are typically diagnosed on neonatal screening but rarely can lie dormant until a metabolic stressor causes initial onset of symptoms in adulthood. A 23-year-old female presented four days postpartum to the emergency department (ED) obtunded and declined to the point of requiring intubation. Labs revealed hyperammonemia, and she was subsequently found to have CTLN1. Urea cycle disorders presenting in adulthood are a rare etiology for the common ED complaint of altered mental status. The low incidence makes these treatable disorders easy to overlook leading to potentially significant morbidity and mortality. Therefore, it is important to recognize the risk factors that can trigger an acute metabolic derangement. This case highlights common risk factors for metabolic stress, possible presenting symptoms, and the positive outcome achievable when recognized and treated in a timely fashion.

Neuropsychological presentation of colpocephaly and porencephaly with symptom onset in adulthood

ABSTRACT Colpocephaly is a form of congenital ventriculomegaly while porencephaly describes any full-thickness defect within the brain which usually presents as a cystic structure. Postulated aetologies include intrauterine/perinatal injuries, genetic disorders, and morphogenesis error. Colopocephaly and porencephaly is typically diagnosed in infancy while diagnosis in adulthood is exceptionally rare. We report a case of co-existence of colpocephaly with porencephaly diagnosed incidentally in a 54-year-old male presenting with subtle cognitive and neurologic abnormalities. Neuropsychological assessment revealed weaknesses in executive functions, processing speed, and language.To our knowledge, this is the only reported case of dual incidental findings of porencephaly and colpocephaly in an adult.

New Approaches to Tay-Sachs Disease Therapy.

Tay-Sachs disease belongs to the group of autosomal-recessive lysosomal storage metabolic disorders. This disease is caused by β-hexosaminidase A (HexA) enzyme deficiency due to various mutations in α-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Tay-Sachs disease is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage and astrocyte activation along with inflammatory mediator production. In most cases, the disease manifests itself during infancy, the “infantile form,” which characterizes the most severe disorders of the nervous system. The juvenile form, the symptoms of which appear in adolescence, and the most rare form with late onset of symptoms in adulthood are also described. The typical features of Tay-Sachs disease are muscle weakness, ataxia, speech, and mental disorders. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, Tay-Sachs disease treatment is based on symptom relief and, in case of the late-onset form, on the delay of progression. There are also clinical reports of substrate reduction therapy using miglustat and bone marrow or hematopoietic stem cell transplantation. At the development stage there are methods of Tay-Sachs disease gene therapy using adeno- or adeno-associated viruses as vectors for the delivery of cDNA encoding α and β HexA subunit genes. Effectiveness of this approach is evaluated in α or β HexA subunit defective model mice or Jacob sheep, in which Tay-Sachs disease arises spontaneously and is characterized by the same pathological features as in humans. This review discusses the possibilities of new therapeutic strategies in Tay-Sachs disease therapy aimed at preventing neurodegeneration and neuroinflammation.

A novel mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitivity to thiazide administration

The clinical phenotypes of patients with Bartter syndrome type III sometimes closely resemble those of Gitelman syndrome. We report a patient with mild, adult-onset symptoms, such as muscular weakness and fatigue, who showed hypokalemic metabolic alkalosis, elevated renin–aldosterone levels with normal blood pressure, hypocalciuria and hypomagnesemia. She was also suffering from chondrocalcinosis. A diuretic test with furosemide and thiazide showed a good response to furosemide, but little response to thiazide. Although the clinical findings and diuretic tests predicted that the patient had Gitelman syndrome, genetic analysis found no mutation in SLC12A3. However, a novel missense mutation, p.L647F in CLCNKB, which is located in the CBS domain at the C-terminus of ClC-Kb, was discovered. Therefore, gene analyses of CLCNKB and SLC12A3 might be necessary to elucidate the precise etiology of the salt-losing tubulopathies regardless of the results of diuretic tests.

A novel m.12908T>A mutation in the mitochondrial ND5 gene in patient with infantile-onset Pompe disease

Pompe disease is a progressive metabolic myopathy caused by deficiency in lysosomal acid α-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of clinical phenotypes exists from hypotonia and severe cardiac hypertrophy in the first few months of life to a milder form with the onset of symptoms in adulthood. The disease is typically due to severe mutations in GAA gene. In the present study, we described a newborn boy with clinical features of Pompe disease particularly with hypertrophic cardiomyopathy, hypotonia and hepatomegaly. This case was at first misdiagnosed as mitochondrial disorder. Accordingly, we performed a mitochondrial mutational analysis that revealed a novel mutation m.12908T>A in the ND5 gene. Secondary structure analysis of the ND5 protein further supported the deleterious role of the m.12908T>A mutation, as it was found to involve an extended imbalance in its hydrophobicity and affect its function.

Congenital Sucrase‐Isomaltase Deficiency

Congenital Sucrase‐Isomaltase Deficiency

Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): raising the bar for diagnosis

Leukoencephalopathy with brain stem and spinal cord involvement and high lactate (LBSL) is an autosomal recessive condition first recognized in 2003, characterized by progressive cerebellar ataxia, spasticity, and frequent involvement of the dorsal columns [1–7]. Decreased mitochondrial aspartyl-tRNA synthetase (mtAspRS) activity secondary to either compound heterozygosity or rarely homozygous mutations involving the DARS2 gene underlie the disease [3, 5–7]. Individuals affected by LBSL show distinctive changes on MRI including diffuse T2 hyperintensities and/or T1 hypointensities involving the cerebral white matter, corticospinal tracts and dorsal columns, variable involvement of the medial lemniscus, cerebellar peduncles, and splenium of the corpus callosum [1–7]. Though an increased lactate peak on MRS is commonly noted in the lesions many individuals with genetically confirmed LBSL fail to show this [1, 2, 4]. Though first described as a progressive disease of childhood onset, five cases with either symptom onset in adulthood or genetic and imaging diagnosis without symptoms have been published (Table 1) [1, 2, 4–6]. We present a patient with symptomatic onset at the age of 35 years, the oldest age of initial symptom manifestations yet described. A 45-year-old female presented for neurological evaluation, because of progressive difficulty walking since the age of 35 years. The patient was born to non-consanguineous parents and has three older asymptomatic siblings. Pregnancy, delivery, and early development were normal. At the age of 35 years, the patient began experiencing right lower extremity spasticity which had slowly progressed over 10 years prior to her initial evaluation. On physical examination mild weakness in the right iliopsoas was noted. There was reduced proprioceptive and vibratory sensation as well as hyperactive reflexes in the lower extremities, right greater than left. The upper extremities were normal. Plantar response was extensor on the right, flexor on the left. There was also an asymmetric spasticity in the lower extremities. An MRI of the spine showed non-enhancing linear T1 hypointensities and T2 hyperintensities involving the bilateral dorsal columns and lateral corticospinal tracts (Fig. 1 a1, b2). MRI of the head showed similar lesions throughout the centrum semiovale, splenium of the corpus callosum, and bilateral corticospinal tracts throughout their course (Fig. 1 c–f). MRS showed no lactate peak, minimal elevation of choline, and normal N-acetyl aspartate. Testing for inflammatory, demyelinating, metabolic, paraneoplastic and infectious etiologies was negative in both serum and cerebrospinal fluid. Because of the symmetry of the lesions noted on MRI a genetic cause was suspected. Mutation analysis of the DARS2 gene revealed a compound heterozygous state for two mutations. The first was a splice site mutation, c.492?2T[C, that has been shown to result in exon skipping within the DARS2 gene and has been previously associated with LBSL [3]. The second was a novel mutation in exon 5 resulting in a valine substitution for a highly conserved glutamic acid at position 158 (c.473A[T, p.Glu158Val) and was predicted by PholyPhen-2 (http:// genetics.bwh.harvard.edu/pph2/dokuwiki/downloads) to Ralitza H. Gavrilova has full access to all of the data and has the right to publish any and all data separate and apart from any sponsor.

The genotype–phenotype correlation in Pompe disease

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that is caused by acid α-glucosidase (GAA) deficiency and is due to pathogenic sequence variations in the corresponding GAA gene. The correlation between genotypes and phenotypes is strict, in that patients with the most severe phenotype, classic infantile Pompe disease, have two pathogenic mutations, one in each GAA allele, that prevent the formation of GAA or totally obliterates its function. All patients with less progressive phenotypes have at least one sequence variation that allows normal or low level synthesis of GAA leading to the formation of analytically measurable, low level GAA activity in most cases. There is an overall trend of finding higher GAA enzyme levels in patients with onset of symptoms in adulthood when compared to patients who show clinical manifestations in early childhood, aged 0-5 years, with a rapidly progressive course, but who lack the severe characteristics of classic infantile Pompe disease. However, several cases have been reported of adult-onset disease with very low GAA activity, which in all those cases corresponds with the GAA genotype. The clinical diversity observed within a large group of patients with functionally the same GAA genotype and the same c.-32-13C > T haplotype demonstrates that modifying factors can have a substantial effect on the clinical course of Pompe disease, disturbing the GAA genotype-phenotype correlation. The present day challenge is to identify these factors and explore them as therapeutic targets.

Pompe disease gene therapy

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

Symptoms of depression and anxiety, and change in body mass index from adolescence to adulthood: results from a British birth cohort

Depression and anxiety have been shown to be associated with obesity and underweight, but little is known about how the relationship varies across the life course, from adolescence through adulthood. We aimed to investigate the association between adolescent- and adult-onset affective symptoms and body mass index (BMI) change from age 15 to 53 years. We used data from a British birth cohort born in 1946 and followed up ever since. The relationship between affective symptom profiles, distinguishing adolescent-onset and adult-onset symptoms, and BMI change from adolescence to age 53 years was investigated using multilevel models. Women with adolescent-onset symptoms had lower mean BMI at age 15 years, faster rates of increase across adulthood, and higher BMI at age 53 years than those with no symptoms. Men with adolescent-onset symptoms had lower BMI at all ages from 15 to 53 years. The BMI trajectories of men and women with adult-onset symptoms did not differ from those with absence of symptoms at all ages. The relationship between affective symptoms and change in BMI varies by sex and age at onset of symptoms. Adolescence may be an important period for the development of the association between affective symptoms and weight gain in girls. Intervention to prevent increases in BMI across adult life in women with adolescent-onset symptoms, even if they are not overweight at this age, should be considered.

Magnetic resonance imaging—based measurements of cerebrospinal fluid and blood flow as indicators of intracranial compliance in patients with Chiari malformation

The diagnosis of Chiari malformation (CM) is based on the degree of tonsilar herniation, although this finding does not necessarily correlate with the presence or absence of symptoms. Intracranial compliance (ICC) and local craniocervical hydrodynamic parameters derived using magnetic resonance (MR) imaging flow measurements were assessed in symptomatic patients and control volunteers to evaluate the role of these factors in the associated pathophysiology. Seventeen healthy volunteers and 34 symptomatic patients with CM were studied using a 1.5-tesla MR imager. Cine phase-contrast images of blood and cerebrospinal fluid (CSF) flow to and from the cranium were used to quantify local hydrodynamic parameters (for example, cord displacement and systolic CSF velocity and flow rates) and ICC. The ICC was derived using a previously described method that measures the small, natural changes in intracranial volume and pressure with each cardiac cycle. Differences in the average cord displacement and systolic CSF velocity and flow, comparing healthy volunteers and patients with CM were not statistically significant. Note, however, that a statistically significant lower ICC (20%) was observed in patients compared with controls. Previous investigators have focused on CSF flow velocities and cord displacement to explain the pathogenesis of CM. Analysis of results have indicated that ICC is more sensitive than local hydrodynamic parameters to changes in the craniospinal biomechanical properties in symptomatic patients. The authors concluded that decreased ICC better explains CM pathophysiology than local hydrodynamic parameters such as cervical CSF velocities and cord displacement. Low ICC also better explains the onset of symptoms in adulthood given the decline in ICC with aging.

Physician awareness of celiac disease: a need for further education.

Celiac disease is a common disorder (up to 0.7%); however, it is uncommonly diagnosed in the United States. We sought to determine physician awareness of celiac disease. Surveys completed by 2,440 (47%) of 5,191 patients in a support group were analyzed for frequency of diagnosis by physician specialties. Questionnaires were then sent to primary care physicians (PCPs) (n=132) in a southern California county to assess knowledge of celiac disease. In patient surveys, only 11% were diagnosed by PCPs (internists and family physicians) versus 65% by gastroenterologists. Physician surveys (70% response) showed that only 35% of PCPs had ever diagnosed celiac disease. Almost all physicians (95%) knew of wheat intolerance, but few (32%) knew that onset of symptoms in adulthood is common. Physicians were well aware (90%) of diarrhea as a symptom, but fewer knew of common symptoms of irritable bowel syndrome (71%), chronic abdominal pain (67%), fatigue (54%), depression and irritability (24%) or of associations with diabetes (13%), anemia (45%) or osteoporosis (45%), or of diagnosis by endomysial antibody tests (44%). Lack of physician awareness of adult onset of symptoms, associated disorders, and use of serology testing may contribute to the underdiagnosis of celiac disease.

A 5-year follow-up study of an atypical case of myotonic dystrophy

This study presents 5-year follow-up data on NG, a woman with adult onset myotonic dystrophy and progressive cognitive decline who was first described by Wilson et al. The extent of the cognitive impairment is atypical of symptom-onset in adulthood and of paternal inheritance, both of which apply to this case. Together, the present and earlier studies report the results of regular neuropsychological assessments over a 16-year period. Severe impairment in executive functioning, episodic and semantic memory were apparent early in the history, while visuospatial skills and working memory were only mildly impaired after 16 years of follow-up. There was also a progressive dyslexia, initially characterized by the regularization errors typical of surface dyslexia, but subsequently dominated by visual/phonological reading errors. This pattern of impairment is not typical of myotonic dystrophy but resembles semantic dementia. Whilst the deficits may be attributable wholly to myotonic dystrophy pathology, the co-existence of a form of semantic dementia is also possible. It is noted that the aggregation of tau protein is a neuropathological feature common to both diseases.

Continuous remodeling of adult extraocular muscles as an explanation for selective craniofacial vulnerability in oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular mystrophy (OPMD) is an inherited disorder caused by mutations of the polyadenylate binding protein nuclear 1 (PABPN1) gene. While a pathogenic hypothesis has been formulated that links the genetic and molecular abnormalities to cellular abnormalities, there is no proven explanation for the targeting of the craniofacial muscles. We propose a hypothesis that bridges this gap. It is based on the phenomenon of continuous remodeling of normal adult extraocular muscles (EOMs). Unlike the EOMs, the myonuclei of other skeletal muscles are postmitotic in the adult unless the muscles are injured. Continuous myofiber remodeling most likely requires upregulation of genes involved in cell cycling, and in protein degradation and synthesis. PABPN1 is a nuclear protein that performs the essential function of controlling polyadenylation of mRNA and the fidelity of protein synthesis. In OPMD, the ongoing production of mutant PABPN1 in muscles undergoing continuous remodeling could result in a failure of accurate production of mRNA required for the maintenance of the myocytes. Over many years, this would lead to cumulative myonuclear loss and finally to myofiber loss. This hypothesis offers an explanation for the selective involvement of extraocular muscles affected in OPMD and the onset of symptoms in adulthood.

The torsional component of "horizontal" congenital nystagmus.

To study the relationship between the major horizontal and minor torsional components of congenital nystagmus to elucidate the diagnostic importance, effects on vision, and pathogenetic implications of the torsional components. We recorded the eye movements of 13 subjects with congenital nystagmus using a three-dimensional magnetic search coil technique over a 15-year period. The subjects fixated on stationary targets straight ahead and along the horizontal and vertical meridians. Six of the 10 subjects with horizontal congenital nystagmus were asymptomatic; the remaining 4 (plus two with a vertical component to their congenital nystagmus) had adult-onset symptoms. An additional subject without symptoms had a vertical congenital nystagmus component plus seesaw nystagmus; one of the symptomatic subjects also had seesaw nystagmus. In all 13 subjects, the horizontal and torsional cycles were phase-locked, and positive horizontal (rightward), vertical (upward, if any), and torsional (clockwise) motion coincided in 10 subjects. That is, rightward horizontal eye rotation coincided with clockwise curvilinear motion (rightward and downward) of the upper pole of each eye. During the horizontal foveation periods, torsional motion was also of low velocity. In 2 of 13 subjects, the torsional waveforms differed from those in the horizontal plane; in others, the direction or the variation with gaze angle differed from that predicted by Listing. In each of the 13 subjects, the torsional components ranged from 8.16% to 94.42% (median, 32.94%) of the peak-to-peak magnitudes of the congenital nystagmus. In most cases, the measured torsion was far greater than that predicted by Listing's law for a worst-case analysis (range, 0.69-11.83%; median, 4.91%). The torsional components of the two subjects with seesaw nystagmus were 60.48% and 264.02%. The manner in which the horizontal and torsional components of "horizontal" congenital nystagmus were phase-locked made clinical detection of the torsional component difficult. Most "horizontal" congenital nystagmus is actually horizontal-torsional congenital nystagmus. Visual acuity during horizontal foveation periods is not significantly diminished by torsional motion. In only one subject did the torsional component of the congenital nystagmus have an amplitude equivalent to Listing torsion; in the other 12 subjects, torsion exceeded our estimate of what Listing's law would predict. The torsional components of the seesaw nystagmus in two subjects also greatly exceeded the torsion predicted by Listing torsion. The most parsimonious explanation for our data is that the cyclic torsion in congenital nystagmus was generated centrally and not a result of Listing torsion, mechanical crosstalk, or normal or abnormal extraocular-muscle (plant) dynamics. Further measurements are needed to confirm this hypothesis.

Genetic testing in spinocerebellar ataxias: defining a clinical role.

Although genetic tests for known spinocerebellar ataxia (SCA) genes are increasingly available, their exact clinical role has received much less attention. Currently available DNA tests can define the genotypes of up to two thirds of patients with dominantly inherited SCAs. Certain characteristic clinical features and ethnic predilection of some of the SCA subtypes may help prioritize specific SCA gene testing. Available data on genotype-phenotype correlation suggest that currently available DNA tests cannot accurately predict age of onset or prognosis. Because of the mostly adult-onset symptoms and the absence of effective treatment, genetic counseling is essential for addressing ethical, social, legal, and psychological issues associated with SCA DNA testing.