Adult-onset Form Research Articles

P.17.6 Globular inclusions are a frequent finding in infantile Pompe’s disease

Pompe’s disease is a clinically and pathologically heterogeneous glycogen storage disease due to mutations in the a-glucosidase gene (GAA). It can be classified into infantile, childhood and adult onset forms. We describe the clinical and pathological spectrum in 4 patients with Pompe’s disease. The first patient presented in the first years of life with hypotonia and respiratory complications. The muscle features contained large vacuoles with increase glycogen and acid phosphatase activity. The second case presented at 13 months with proximal muscle weakness. His muscle biopsy showed small vacuoles in few fibres.Vacuolated fibres showed acid phosphatase activity and contained increased glycogen. These findings were confirmed with electron-microscopy. In addition we observed acid phosphatase positive globular inclusions. The third patient presented with mild hypotonia and hyperlaxity of proximal joints at the age of one. At this age muscle biopsy showed acid phosphatase positive/PAS negative inclusions as the main pathological sign in 3% of muscle fibres on average although it varied from one area to another of the section. In addition it showed small vacuoles in a few isolated fibers. There was some glycogen accumulation in some fibres although it did not always correspond to the vacuolated areas. The fourth case was asymptomatic apart from elevated CK levels which were detected on a routine analysis. His muscle biopsy did not show abnormalities at the light or ultrastructural levels. These data show that globular inclusions, previously only described in adults, can also be frequently observed in infantile Pompe’s patients and that they can be found by their own or in combination with vacuoles. The presence of these inclusions may be associated with the disease progression or with the specific mutations. Further studies are needed to elucidate the formation of these inclusions and how their relationship with a-glucosidase deficiency.

P.9.1 Clinical and histopathological features of nemaline myopathy

Nemaline myopathies are a heterogeneous group of myopathies characterized by presence of rod-like structures in skeletal muscle. Most patients have a congenital onset but clinical presentation can vary from severe fetal akinesia sequence to mild childhood-onset and even adult-onset forms. Genetic heterogeneity and overlap with other myopathies are well-known. We have evaluated clinical and histopathological features of nemaline myopathy cases diagnosed in our center between 2003 and 2013. There were 29 non-related cases (M:F = 1.2:1), age of biopsy ranging from 15 days to 16 yr. Onset of symptoms was in the newborn period in 12 cases (41%) and 18 cases (60%) were

Autonomic dysfunction in adult-onset alexander disease

Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.

Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed.

Description of the first two cases of Pompe disease in Bulgaria

Pompe disease is a rare, metabolic, multi-system, lysosomal storage disorder with autosomal recessive inheritance, caused by a deficiency of the glycogen-degrading lysosomal enzyme, acid alpha-glucosidase (GAA). Great phenotypic variability has led to the classification of several subtypes: infantile, late-infantile, childhood, juvenile, and adult-onset form, based on the age of onset and degree of organ involvement. In the most severe cases, disease onset is in infancy and death results from cardiac and respiratory failure along with muscle weakness within the first one or two years of life. In the milder, late-onset forms, muscle weakness is the primary symptom. Weakness of respiratory muscles is the major cause of mortality in these cases.

Management of Trigeminal Autonomic Cephalalgias in Children and Adolescents

Primary headache disorders that are more frequently encountered in the paediatric population include migraine and tension-type headaches. The trigeminal autonomic cephalalgias (TACs), which includes cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), are rarely reported in the paediatric population. The 1-year prevalence of CH seems to be 0.03 %. The clinical features of childhood and adolescence onset CH seem to be similar to those of adult onset. Cranial autonomic features and restlessness seem to less prominent in children than in adults. When restlessness is present, it often manifests as thrashing around in children and can distract attention from the headache, thereby contributing to a delay in diagnosis. The frequency of cluster periods seems to be lower in childhood. Similarly, the duration of the single cluster period seems to be shorter. The temporal pattern shows a trend towards a gradual increase of frequency and duration of symptoms in adult life. In terms of management of paediatric CH, oxygen has been used successfully in several paediatric CH patients, and given its good side-effect profile, it is considered the abortive agent of choice for paediatric CH. Verapamil is the preventative drug of choice in both episodic and chronic CH, though paediatric patients should be started on lower doses and titrated according to age. Paediatric-onset PH and SUNCT are very rarely reported. The clinical phenotype and response to treatment seem to resemble the adult-onset form. Paediatric-onset TACs are poorly recognized and there is often a delay of several months or years before the diagnosis is made. Awareness of typical clinical pictures of these excruciating headaches is essential to allow prompt initiation of the appropriate management.

The first inborn error of manganese metabolism caused by mutations in SLC30A10, a newly identified manganese transporter

BackgroundWe have identified an autosomal recessively inherited disorder of manganese metabolism that causes manganese accumulation in liver and brain with characteristic MRI brain appearances of hyperintense basal ganglia on T1-weighted sequences. Most affected individuals present in childhood with difficulties walking and fine motor impairment due to dystonia. Movement disorder is accompanied by liver cirrhosis, and some patients have died at a young age following complications of cirrhosis. An adult-onset form of parkinsonism associated with hepatomegaly and hypermanganesaemia has also been described. Further characteristics of both phenotypes include polycythaemia and features of iron depletion. MethodsHomozygosity mapping was performed using an Illumina CytoSNP-12. The candidate gene was sequenced on an ABI sequencer. Functional studies in the manganese-sensitive yeast strain Δpmr1 were performed using Gateway technology (Invitrogen). FindingsHomozygosity mapping identified SLC30A10 as the affected gene, and homozygous sequence changes were found in all affected individuals. SLC30A10 had previously been presumed to belong to a class of zinc transporters. However, expression of human wildtype SLC30A10 in Δpmr1 rescued growth in high manganese conditions confirming its role in manganese transport. The presence of missense and nonsense mutations in SLC30A10 failed to restore manganese resistance. InterpretationEvidently, evolutionary changes in the aminoacid sequence have altered the substrate specificity of this transporter from zinc in yeast to manganese in mammalian cells. SLC30A10 is the first recognised human manganese transporter that, when defective, causes two distinct phenotypes—childhood onset dystonia and adult onset parkinsonism—that are associated with hepatic cirrhosis and polycythaemia. Present treatment strategies, including chelation therapy with disodium calcium edetate and iron supplementation, lead to significant improvement of clinical symptoms and blood manganese levels. FundingAction Medical Research.

The broad clinical phenotype of Type 1 diabetes at presentation

Immune-mediated (auto-immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. Indeed, as the adult-onset form of autoimmune diabetes may resemble Type 2 diabetes, it is imperative to test for diabetes-associated autoantibodies to establish the correct diagnosis. The therapeutic response can be predicted by measuring the levels of autoantibodies to various islet cell autoantigens, such as islet cell antibodies (ICA), glutamate decarboxylase 65 (GAD65), insulin, tyrosine phosphatase (IA-2) and IA-2β, and zinc transporter 8 (ZnT8) and evaluating β-cell function. A high risk of progression to insulin dependency is associated with particular genetic constellations, such as human leukocyte antigen risk alleles, young age at onset, the presence of multiple autoantibodies, including high titres of anti-GAD antibodies; such patients should be offered early insulin replacement therapy, as they respond poorly to diet and oral hypoglycaemic drug therapy. Hence, considering the broad spectrum of phenotypes seen in adult-onset diabetes, treatment targets can only be reached by identification of immune-mediated cases, as their management differs from those with classical Type 2 diabetes.

Childhood Ataxia With Central Nervous System Hypomyelination: A Report of First Two Cases With Juvenile and Adult - Onset Forms in a Turkish Family

Childhood ataxia with central nervous system hypomyelination (CACH)) is an inherited autosomal recessive white matter disease which is also known as leukoencephalopathy with vanishing white matter (VWM). Ataxia and spasticity are the predominant symptoms of the disease. It is a progressive disease with exacerbations. Manyetic resonance imaging (MRI) is diagnostic with diffuse white matter abnormalities. It can be seen at all ages but adult forms are rare. We report here the first two cases of juvenile and adult-onset forms of the disease in Turkey. They are two sisters with age of 21 and 25 who presented us with gait difficulty and spasticity. They had seizures and also the typical MRI findings of CACH. We should consider it in the differential diagnosis of gait difficulty, ataxia and spasticity in adult patients. doi: http://dx.doi.org/10.4021/jnr162w

Recurrent mutations inDNAJC5cause autosomal dominant Kufs disease

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

G.P.112 The diagnostic pathway in adult onset Pompe disease

Abstract Pompe disease (PD) is an autosomal recessive disease due to a deficiency in lysosomal acid α glucosidase (GAA). The adult onset form is characterized by progressive weakness in limb, axial and respiratory muscles leading to motor disability and respiratory failure. The existence of enzyme replacement therapy (ERT) necessitates a rapid recognition of this disease because starting the treatment at an early stage can delay or stop its natural progression. Initial symptoms can be subtle and difficult to recognize. This results in significant diagnosis delays (over 10 years). In more advanced stages PD may resemble other neuromuscular diseases. In order to learn more about the diagnostic process in PD, we conducted a telephone survey. Nineteen patients (age 17–81) with confirmed PD and/or their close relatives were interviewed in order to understand diagnostic paths and difficulties. In 78% of the cases the diagnosis was made by a neurologist. Patients consulted as many as six different specialists before diagnosis (0.7 visits/year average). 53% to a GP in the first consultation. Delay for diagnosis ranged from 2.5 months to 40 years. The method most often used for diagnosis was enzyme assay in lymphocytes. There was no suspicion of the diagnosis unless VC was significantly reduced or there was respiratory insufficiency. Main diagnoses evoked were herniated disk, multiple sclerosis, anorexia nervosa, myositis, tiredness, muscular dystrophy, chronic fatigue syndrome among others. AOPD may present in many different ways. Many different specialists are consulted for different symptoms and the diagnosis pathway can be followed. Delays in diagnosis can run up to decades. Many conclusions can be drawn from this type of survey, which may help in the future to detect patients in early stages of the disease when they could obtain greater benefit from treatment.

The adult polyglucosan body disease mutation GBE1 c.1076A>C occurs at high frequency in persons of Ashkenazi Jewish background

Mutations of the glycogen branching enzyme gene, GBE1, result in glycogen storage disease (GSD) type IV, an autosomal recessive disorder having multiple clinical forms. One mutant allele of this gene, GBE1 c.1076A>C, has been reported in Ashkenazi Jewish cases of an adult-onset form of GSD type IV, adult polyglucosan body disease (APBD), but no epidemiological analyses of this mutation have been performed. We report here the first epidemiological study of this mutation in persons of Ashkenazi Jewish background and find that this mutation has a gene frequency of 1 in 34.5 (95% CI: 0.0145-0.0512), similar to the frequency of the common mutation causing Tay-Sachs disease among Ashkenazi Jews. This finding reveals APBD to be another monogenic disorder that occurs with increased frequency in persons of Ashkenazi Jewish ancestry.

Family Treatment for Bipolar Disorder and Substance Abuse in Late Adolescence

The initial onset of bipolar disorder occurs in childhood or adolescence in about 50% of patients. Early-onset forms of the disorder have a poorer prognosis than adult-onset forms and are frequently characterized by comorbid substance abuse. Clinical trials research suggests that family psychoeducational approaches are effective adjuncts to medication in stabilizing the symptoms of bipolar disorder in adults and youth, although their efficacy in patients with comorbid substance use disorders has not been systematically investigated. This article describes the family-focused treatment (FFT) of a late adolescent with bipolar disorder and polysubstance dependence. The treatment of this patient and family required adapting FFT to consider the family's structure, dysfunctional alliance patterns, and unresolved conflicts from early in the family's history. The case illustrates the importance of conducting manual-based behavioral family treatments with a psychotherapeutic attitude, including addressing unstated emotional conflicts and resistances that may impede progress.

Treatment of demodicosis in dogs: 2011 clinical practice guidelines

These guidelines were written by an international group of specialists with the aim to provide veterinarians with current recommendations for the diagnosis and treatment of canine demodicosis. Published studies of the various treatment options were reviewed and summarized. Where evidence in form of published studies was not available, expert consensus formed the base of the recommendations. Demodicosis can usually be diagnosed by deep skin scrapings or trichograms; in rare cases a skin biopsy may be needed for diagnosis. Immune suppression due to endoparasitism or malnutrition in young dogs and endocrine diseases, neoplasia and chemotherapy in older dogs are considered predisposing factors and should be diagnosed and treated to optimize the therapeutic outcome. Dogs with disease severity requiring parasiticidal therapy should not be bred. Secondary bacterial skin infections frequently complicate the disease and require topical and/or systemic antimicrobial therapy. There is good evidence for the efficacy of weekly amitraz rinses and daily oral macrocyclic lactones such as milbemycin oxime, ivermectin and moxidectin for the treatment of canine demodicosis. Weekly application of topical moxidectin can be useful in dogs with milder forms of the disease. There is some evidence for the efficacy of weekly or twice weekly subcutaneous or oral doramectin. Systemic macrocyclic lactones may cause neurological adverse effects in sensitive dogs, thus a gradual increase to the final therapeutic dose may be prudent (particularly in herding breeds). Treatment should be monitored with monthly skin scrapings and extended beyond clinical and microscopic cure to minimize recurrences.

The new era of Pompe disease: Advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management

Pompe disease is an autosomal recessive neuromuscular disorder marked by progressive muscle weakness due to lysosomal buildup of glycogen. Presentation is described as a spectrum, varying by age of onset, organ involvement, and degree of myopathy. Given the phenotypic variability, Pompe disease is broadly classified into an infantile form and a late onset (juvenile, childhood, adult onset) form. Prior to the advent of enzyme replacement therapy (ERT) with alglucosidase alfa and approval for human use in 2006, the natural history was limited due to death before age 2 years for infantile onset cases and significant morbidity and early mortality for late onset Pompe disease (LOPD). ERT with alglucosidase alfa redefined the once fatal outcome in infantile Pompe, establishing an emergent phenotype. Treatment in late onset patients resulted in improved outcomes, enhancing understanding of the phenotype, presentation, and extent of organ involvement. This Issue of the Seminars seeks to enumerate the recent advancements in the field of Pompe disease, including newborn screening, novel therapeutic targets, new insights in the pathophysiology including role of autophagy, and impacts of long-term disease burden and CNS glycogen accumulation on cognition in infantile survivors. It also addresses immunological challenges and the critical role of immunomodulation in ERT treatment outcome. Other topics discussed include the role of biomarkers in monitoring disease progression and treatment responses, the role of genotype in defining phenotype and treatment response, better insights into the clinical presentations in LOPD and finally the importance of a multidisciplinary approach to care with the role of physical therapy as an example. Many gaps in our scientific understanding of this disease still remain; however, we hope the next decade will bring new knowledge and therapies to the horizon.

Mutations in the Gene DNAJC5 Cause Autosomal Dominant Kufs Disease in a Proportion of Cases: Study of the Parry Family and 8 Other Families

BackgroundThe Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD).Methodology and Principal FindingsWe have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment.ConclusionsOur study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.

Childhood Ataxia With Central Nervous System Hypomyelination: A Report of First Two Cases With Juvenile and Adult - Onset Forms in a Turkish Family

Childhood ataxia with central nervous system hypomyelination (CACH)) is an inherited autosomal recessive white matter disease which is also known as leukoencephalopathy with vanishing white matter (VWM). Ataxia and spasticity are the predominant symptoms of the disease. It is a progressive disease with exacerbations. Manyetic resonance imaging (MRI) is diagnostic with diffuse white matter abnormalities. It can be seen at all ages but adult forms are rare. We report here the first two cases of juvenile and adult-onset forms of the disease in Turkey. They are two sisters with age of 21 and 25 who presented us with gait difficulty and spasticity. They had seizures and also the typical MRI findings of CACH. We should consider it in the differential diagnosis of gait difficulty, ataxia and spasticity in adult patients. J Neurol Res. 2012;2(6):250-254 doi: https://doi.org/10.4021/jnr162w

P3.8 Cardiac involvement in patients with spinal muscular atrophies

The spinal muscular atrophies (SMAs) comprise a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: acute infantile (SMA type I), chronic infantile (type II), chronic juvenile (SMA type), and adult onset (SMA type IV) forms. The incidence is about 1:10,000 live births with a carrier frequency of 1:50. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset.

Clinical manifestation, disease course and response to enzyme replacement therapy in Hungarian patients with Pompe’s disease

Pompe’s disease is an autosomal recessive disease caused by deficiency of acid-alpha-glucosidase. Aims and Methods: Authors analyzed the phenotype of 11 Hungarian patients with Pompe’s disease and evaluated clinical parameters and response to enzyme replacement therapy during a long-term follow-up in 8 patients. Results: One patient with atypical infantile form presented with cardiomyopathy and a very slow progression of motor deficits; after 2 years of enzyme replacement therapy no disability was present at the age 6 years. Another patient was asymptomatic at the age of 2.5 years. The adult onset form was characterized by slight to prominent limb-girdle myopathy with an age of onset between 20 and 50 years. In 3 of such cases respiratory insufficiency was also present. Conclusions: Hungarian patients with Pompe’s disease presented with a wide phenotypic variability ranging from atypical early childhood form with slowly progressive course to late-onset limb-girdle myopathy with variable courses. Enzyme replacement therapy resulted in significant improvement in motor and respiratory functions in most of the patients. Orv. Hetil., 2011, 152, 1569–1575.