A New Era in Pathology Consultation: The MyPathologist Electronic Consultation Tool.

Pathologists and laboratory scientists provide valuable guidance on laboratory utilization, test ordering, interpretation, and quality control provided that clinical staff can easily access the laboratory team. To encourage consultation between clinicians with laboratory scientists and pathologists, we developed an easily accessible electronic tool termed "MyPathologist," placed on the homepage of our electronic health record system. Over its 2-year pilot, utilization of this consultation tool climbed as we continued to publicize it and incorporated education into housestaff onboarding and electronic health record training. Physician satisfaction with the tool was high. Additionally, this became the primary source of consults to our residency call service. Evaluation of MyPathologist questions received during its pilot period showed that more than half the questions were of significant educational value to the residents, often focusing on results interpretation, appropriate test ordering, and quality control. MyPathologist is a novel electronic tool for pathology consultation within our electronic health record and also represents an avenue for educating residents, improving utilization of the laboratory, and improving patient care.

Abdominal Angiostrongyliasis: A Presentation of Eosinophilic Granulomatous Colitis.

We present a case of a 4-year-old girl with abdominal angiostrongyliasis who presented with persistent fevers, hepatosplenomegaly, acute abdominal pain, and eosinophilia. Computed tomography scan identified thickening of the ascending colon with a narrowed lumen. Endoscopic evaluation revealed ulcerations and erythema in the ascending colon. The microscopic findings in biopsies included active chronic inflammation with prominent eosinophils and granulomas. A subset of granulomas contained the eggs of Angiostrongylus costaricensis. The definitive method of diagnosing A costaricensis is histology; peripheral blood serology has low specificity and the stool from infected patients does not contain eggs or larvae. Pathologists from endemic regions (Central and South America) are familiar with the typical histologic changes; however, because of increasing global travel, all pathologists should become familiar with A costaricensis, which may mimic common gastrointestinal diseases such as Crohn's disease, appendicitis, and Meckel's diverticulum.

Clinical features of the myasthenic syndrome arising from mutations in GMPPB.

BACKGROUND: Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission. METHODS: Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity. RESULTS: All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol. CONCLUSIONS: Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.

Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Clinicopathologic findings in (anti-FcepsilonR1alpha) autoimmune-related chronic urticaria.

BACKGROUND: One cause of chronic urticaria is autoreactivity which is diagnosed by detecting autoantibodies against the IgE receptor alpha subunit (anti-Fc R1alpha). OBJECTIVE: To compare the histopathologic features of chronic urticaria patients testing positive for anti-IgE receptor antibody (Ab) to those testing negative. METHODS: Totally, 438 patients with a clinical presentation of chronic urticaria (2011-2013) had anti-IgE receptor Ab tested and 37 of those patients had skin biopsy. We evaluated microscopic features including: spongiosis, dermal edema, presence of mast cells, density of lymphocytic infiltration, predomination of eosinophils/neutrophils; intravascular neutrophils and presence of vasculitis. The aforementioned features were compared between negative and positive anti-IgE receptor Ab groups. RESULTS: Of 37 patients , 69% were women and 31% were men. 49% had positive anti-IgE receptor Ab and 51% had negative anti-IgE receptor Ab. In the positive anti-IgE receptor Ab group, 83% showed intravascular neutrophils. Eosinophil predominance was identified in 72% and neutrophil predominance was identified in 28%. In the negative anti-IgE receptor Ab group, 89% showed intravascular neutrophils. Eosinophil predominance was identified in 53% and neutrophil predominance was identified in 47%. There was no evidence of vasculitis in either group. CONCLUSION: There were no significant histopathologic differences between the anti-IgE receptor Ab positive and negative cases. Therefore, serum testing for anti-IgE receptor Ab is required to identify this subgroup of chronic urticaria patients.

Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1.

BACKGROUND: A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. METHODS: We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. RESULTS: Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. CONCLUSIONS: These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.

Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates.

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.

Motor neuron disease in a patient with a mitochondrial tRNAIle mutation.

OBJECTIVE: Motor neuron disease (MND) is a common neurodegenerative condition for which the underlying cause is uncertain in many patients. We identified a patient with clinical features suggestive of MND but additional cardiac and metabolic symptoms. We wished to determine if the clinical features were due to a mitochondrial DNA mutation. METHODS: The brain and spinal cord were studied using neuropathological techniques and agenetic defect investigated in individual neurons. RESULTS: There were atypical neuropathological features and genetic studies identified a pathogenic, heteroplasmic mitochondria tRNA(Ile) (4274T>C) mutation. INTERPRETATION: This case adds to the phenotypic variation seen in mitochondrial DNA disease but also highlights the potential role of mitochondrial dysfunction in the cause of MND.

Minimum prevalence of spinocerebellar ataxia 17 in the north east of England.

OBJECTIVE: To determine the minimum prevalence of spinocerebellar ataxia type 17 (SCA17) in the north east of England. PATIENTS AND METHODS: A defined region containing 2,516,500 individuals with 192 families with undiagnosed ataxia, 90 patients with a Huntington's disease-like phenotype and 292 controls. The number of (CAG/CAA)(n) repeats in the SCA17/TBP gene was determined by fluorescent PCR and sequenced in affected individuals. RESULTS: The mean repeat size for 584 control alleles was 34 (S.D.=3.58), ranging from 25 to 40. Two index cases had larger alleles with repeat lengths greater than the control range. Affected family members presented in adult life with ataxia followed by extrapyramidal features and cognitive impairment. In one family 44 repeats were associated with a younger age of onset than has been previously described. CONCLUSIONS: The minimum prevalence of SCA17 in the north east of England was 0.16/100,000 (upper 95% confidence interval 0.31/100,000).

Spectrum of movement disorders in neuroferritinopathy.

Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic-rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.

Normokalemic periodic paralysis revisited: does it exist?

Normokalemic periodic paralysis (normoKPP) is well established in the literature, but there are doubts as to whether it exists as a discrete entity. Retrospective clinical and molecular analysis has confirmed suspicions that most normoKPP families actually have a variant of hyperkalemic periodic paralysis (hyperKPP) due to a mutation of the muscle-specific sodium channel gene (SCN4A). However, the original normoKPP family described by Poskanzer and Kerr (Poskanzer DC, Kerr DNS. A third type of periodic paralysis, with normokalemia and favourable response to sodium chloride. Am J Med 1961;31:328-342) has remained unchallenged. We identified the Met1592Val mutation of SCN4A in an affected descendent of this original normoKPP family. This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.