The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself. Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy.     

Autism spectrum disorders: The quest for genetic syndromes

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader–Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.     

Central nervous system involvement in patients with acute myeloid leukemia

Background/aim To evaluate the incidence, clinical features, risk factors, and prognosis of central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML).Materials and methodsAll AML patients who were admitted to Hacettepe University hospital between 2000 and 2021 were evaluated. The medical records of 548 AML cases were retrospectively analyzed. Results The frequency of CNS involvement was 2.4% (n = 13) at diagnosis and 4.6% (n = 25) at diagnosis or during follow-up. Parenchymal involvement was seen in 5 patients, leptomeningeal involvement was seen in 11 patients. Three patients had both leptomeningeal and parenchymal involvements, and 6 patients had optic nerve or ocular involvement. In univariate analysis, younger age and extramedullary involvement at diagnosis were associated with CNS disease at diagnosis, and extramedullary involvement at diagnosis was associated with CNS disease during follow-up. In multivariate analysis; younger age and extramedullary involvement at diagnosis were associated with CNS disease at diagnosis and during follow-up respectively. Median overall survival was 5.4 months in patients with CNS disease at diagnosis and 16.9 months in patients with CNS disease during follow-up and 16.2 months in patients with no CNS disease.Conclusion CNS disease is a rare complication of AML. Younger age and extramedullary involvement at diagnosis are risk factors for CNS involvement.     

Brain white matter abnormalities associated with copy number variants

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro‐rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro‐rearrangement syndrome, and a chromosomal microarray analysis should be performed.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients with Central Nervous System Involvement

Central nervous system (CNS) involvement in adult acute myeloid leukemia (AML) is rare and associated with poor outcomes. Therefore, CNS involvement in AML is an indicator for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the impact of CNS involvement in AML on the outcome of allo-HSCT remains unclear. We performed a large-scale nationwide retrospective analysis to elucidate the outcomes of allo-HSCT on AML with CNS involvement (CNS+AML). Clinical data were collected from a registry database of the Japan Society for Hematopoietic Cell Transplantation. CNS involvement was defined as the infiltration of leukemia cells into the CNS or myeloid sarcoma in the CNS identified at any time from diagnosis to transplantation. One hundred fifty-seven patients with CNS+AML underwent allo-HSCT between 2006 and 2011. The estimated overall survival, cumulative incidence of relapse and nonrelapse mortality at 2 years for CNS+AML (51.2%, 30.2%, and 14.5%, respectively) were comparable with those for AML without CNS involvement (48.6%, 27.4%, and 22.0%, respectively). Univariate and multivariate analyses indicated that the development of chronic graft-versus-host disease, disease status, and cytogenetic risk category were independent prognostic factors for overall survival for CNS+AML. These results suggest that allo-HSCT may improve outcomes in patients with CNS+AML.     

Mutations in ERGIC1 cause Arthrogryposis multiplex congenita,neuropathic type

Arthrogryposis multiplex congenita (AMC) is heterogeneous group of disorders characterized by non‐progressive joint contractures from birth that involve more than 1 part of the body. There are various etiologies for AMC including genetic and environmental depends on the specific type, however, for most types, the cause is not fully understood. We previously reported large Israeli Arab kindred consisting of 16 patients affected with AMC neuropathic type, and mapped the locus to a 5.5 cM interval on chromosome 5qter. Using whole exome sequencing, we have now identified homozygous pathogenic variant in the ERGIC1 gene within the previously defined linked region. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. We further show that this mutation was absent in more than 200 samples of healthy unrelated individuals of the Israeli Arab population. Thus, our findings expand the spectrum of hereditary AMC and suggest that abnormalities in protein trafficking may underlie AMC‐related disorders.     

Gene networks associated with non-syndromic intellectual disability

Non-syndromic intellectual disability (NS-ID) is a genetically heterogeneous disorder, with more than 200 candidate genes to date. Despite the increasing number of novel mutations detected, a relatively low number of recurrently mutated genes have been identified, highlighting the complex genetic architecture of the disorder. A systematic search of PubMed and Medline identified 245 genes harbouring non-synonymous variants, insertions or deletions, which were identified as candidate NS-ID genes from case reports or from linkage or pedigree analyses. From this list, 33 genes are common to syndromic intellectual disability (S-ID) and 58 genes are common to certain neurological and neuropsychiatric disorders that often include intellectual disability as a clinical feature. We examined the evolutionary constraint and brain expression of these gene sets, and we performed gene network and protein–protein interaction analyses using GeneGO MetaCore^TM and DAPPLE, respectively. The 245?NS-ID candidate genes were over-represented in axon guidance, synaptogenesis, cell adhesion and neurotransmission pathways, all of which are key neurodevelopmental processes for the establishment of mature neuronal circuitry in the brain. These 245 genes exhibit significantly elevated expression in human brain and are evolutionarily constrained, consistent with expectations for a brain disorder such as NS-ID that is associated with reduced fecundity. In addition, we report enrichment of dopaminergic and glutamatergic pathways for those candidate NS-ID genes that are common to S-ID and/or neurological and neuropsychiatric disorders that exhibit intellectual disability. Collectively, this study provides an overview and analysis of gene networks associated with NS-ID and suggests modulation of neurotransmission, particularly dopaminergic and glutamatergic systems as key contributors to synaptic dysfunction in NS-ID.     

Hepatitic inherited metabolic disorders

Primary metabolic disorders are a disparate group of diseases that may or may not be accompanied by hepatic manifestations. Those with liver involvement may show a range of histopathologic changes. Proper histologic diagnosis requires correlation with clinical and laboratory data, including evaluation for mutations either via serum protein electrophoresis or through formal genetic analysis. This article is a review of the three most common inherited metabolic disorders which may present with a hepatitic pattern. In alpha1-antitrypsin disorder, there is a broad range of clinical presentations, age at presentation, and histological features ranging from "neonatal hepatitis" to a chronic progressive hepatitis in later childhood and adulthood. Hence, this disorder must be in the differential diagnosis of liver disease of the very young, and in older children and adults, with or without coexistent overt pulmonary symptoms. In Wilson disease, presentation tends to be in older childhood or the adult, with a progressive chronic hepatitis. Cystic fibrosis may feature a characteristic obstructive biliary syndrome, coexisting with the many extrahepatic manifestations of this debilitating disease. Lastly, the progressive familial intrahepatic cholestasis (PFIC) syndromes are given as examples of inherited metabolic conditions in which relentlessly progressive cholestatic liver disease eventuates over years in end-stage cholestatic liver disease with cirrhosis. Distinguishing features include absence of elevated serum gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, and elevated GGT in PFIC-3. However, molecular studies are required for a confident diagnosis of the rare PFIC syndromes.     

Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy

Methyl-CpG-binding domain 5 (MBD5)-associated neurodevelopmental disorder caused by 2q23.1 or MBD5-specific mutation has been recently identified as a genetic disorder associated with autism spectrum disorders. Phenotypic features of 2q23.1 deletion or disruption of MBD5 gene include severe intellectual disability, seizure, significant speech impairment, sleep disturbance, and autistic-like behavioural problems. Here we report a 7-year-old girl with intellectual disability and epilepsy without previous clinical diagnosis. Diagnostic exome sequencing identified a novel frameshift mutation c.254_255delGA (p.Arg85Asnfs*6) in the MBD5 gene of the proband and her father. The proband's father with normal intelligence showed subclinical manifestations observed in subsequent investigations. Clinical manifestations, disease course, and molecular findings of the involvement of MBD5 gene in this family suggest an unusual MBD5-related neurodevelopmental disorder. Moreover, this report demonstrates the critical role of next-generation sequencing technique in characterizing such a rare disorder with variable or no clinical manifestation and providing opportunity to develop effective preventive measures such as pre-implantation genetic diagnosis.     

Complex I deficiency: clinical features, biochemistry and molecular genetics

Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ～25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.     

X-linked malformations of cortical development.

Disorders of the development of the human cortex are recognized as significant causes of mental retardation, epilepsy, and congenital neurologic deficits. These malformations may be restricted to the brain or may be one component of a generalized malformation syndrome. Through the efforts of several groups, a large number of human cortical malformations have been identified and classified. Studies of informative families and sporadic patients with specific chromosomal rearrangements or deletions have demonstrated a genetic basis for many of these disorders. Subsequent work has facilitated a precise genetic diagnosis and provided insight into the molecular basis of some of these malformations. This review will discuss four cortical malformation syndromes, which are known or likely to have an X-linked inheritance pattern: bilateral periventricular nodular heterotopia, X-linked lissencephaly/subcortical band heterotopia, X-linked lissencephaly with abnormal genitalia, and X-linked bilateral perisylvian polymicrogyria.     

Influence of sympathetic nervous system on sensorimotor function: whiplash associated disorders (WAD) as a model

There is increasing interest about the possible involvement of the sympathetic nervous system (SNS) in initiation and maintenance of chronic muscle pain syndromes of different aetiology. Epidemiological data show that stresses of different nature, e.g. work-related, psychosocial, etc., typically characterised by SNS activation, may be a co-factor in the development of the pain syndrome and/or negatively affect its time course. In spite of their clear traumatic origin, whiplash associated disorders (WAD) appear to share many common features with other chronic pain syndromes affecting the musculo-skeletal system. These features do not only include symptoms, like type of pain or sensory and motor dysfunctions, but possibly also some of the pathophysiological mechanisms that may concur to establish the chronic pain syndrome. This review focuses on WAD, particular emphasis being devoted to sensorimotor symptoms, and on the actions exerted by the sympathetic system at muscle level. Besides its well-known action on muscle blood flow, the SNS is able to affect the contractility of muscle fibres, to modulate the proprioceptive information arising from the muscle spindle receptors and, under certain conditions, to modulate nociceptive information. Furthermore, the activity of the SNS itself is in turn affected by muscle conditions, such as its current state of activity, fatigue and pain signals originating in the muscle. The possible involvement of the SNS in the development of WAD is discussed in light of the several positive feedback loops in which it is implicated.     

Stratégie diagnostique dans les maladies mitochondriales

Mitochondrial diseases (MD) are the most frequent metabolic disorders. They have in common a respiratory chain deficiency. Clinical presentation of MD is very heterogeneous and the major physiological functions may be affected. Diagnosis is complex due to the potential involvement of two genomes (nuclear or mitochondrial DNA), the large number of candidate genes to screen and the small number of patients reported for each type of MD. Clinical presentation, trait of inheritance, cerebral imaging (MRI and CT-Scan) and specialized biochemical investigations are good indicators, but identification of causing mutation(s) is the clue to confirm diagnosis. Task is huge and progress in diagnosis of MD should come from genotype-phenotype correlations studies and from major technical improvements in molecular diagnosis. Exhaustive study of mitochondrial DNA is the first necessary step that is now possible with methods like Surveyor and Affymetrix resequencing chip. Combination of data including clinical informations, cerebral imaging, respiratory chain deficiency and/or assembly profile of respiratory chain complexes (BN-PAGE profile) may contribute for orientation for nuclear DNA studies. Elucidation of the genetic bases of MD is important for patients: identification of causing mutation(s) allows offering genetic counselling and possibility of prenatal diagnosis.     

Identificación y utilidad clínica de los anticuerpos antineuronales

We review the neuronal antibodies described in CNS disorders in order to clarify their diagnostic value. In this work, the neuronal antibodies associated with syndromes resulting from CNS neuronal dysfunction were classified into two groups according to the location of the antigen inside the neuron or in the cell membrane. Group I includes antibodies that target intracellular antigens and are probably not pathogenic. They include onconeural antibodies (Hu [ANNA1], Yo [PCA1], Ri [ANNA2], CV2 [CRMP5], amphiphysin, Ma2, Tr, SOX1), which are useful for the diagnosis of paraneoplastic neurological syndromes (PNS). Other antibodies of this group, mainly anti-glutamic acid decarboxylase (GAD) antibodies, identify non-paraneoplastic syndromes (PNS), such as stiff-person syndrome (SPS), cerebellar ataxia, and limbic encephalitis (LE). Group II antibodies recognize neuronal surface antigens. Antibodies in this group are associated with characteristic CNS syndromes, but their detection does not indicate that the disorder is paraneoplastic. The most frequent are the anti-receptor NMDA antibodies, followed by the antibodies against the protein LGI1 associated with the potassium channel. Other less common antibodies include those against the receptors of AMPA, GABAb, mGluR 1 and 5, and against CASPR2. A pathogenic role of the antibodies is suggested by the response of symptoms to immunotherapy, and the correlation between antibody titers and neurological outcome.     

Multiple cranial neuropathy: a common diagnostic problem

Syndrome of multiple cranial palsies is a common clinical problem routinely encountered in neurological practice. Anatomical patterns of cranial nerves involvement help in localizing the lesion. Various infections, malignant neoplasms and autoimmune vasculitis are common disorders leading to various syndromes of multiple cranial nerve palsies. A large number of diffuse neurological disorders (e.g. Gullian-Barre syndrome, myopathies) may also present with syndrome of multiple cranial nerve palsies. Despite extensive biochemical and radiological work-up the accurate diagnosis may not be established. Few such patients represent "idiopathic" variety of multiple cranial nerve involvement and show good response to corticosteroids. Widespread and sequential involvements of cranial nerves frequently suggest possibility of malignant infiltration of meninges, however, confirmation of diagnosis may not be possible before autopsy.     

Mitochondrial myopathies-clinicopathological features and diagnostic modalities

Mitochondrial myopathy is the term applied to a clinically and biochemically heterogeneous group of disorders which have multisystem involvement. The concept was introduced by Luft in 1962. These are due to genetic defects in the respiratory chain enzymes which are detected by histochemical, immunohistochemical stains, molecular biological studies and ultrastructural studies on muscle biopsy. Classification of the disorders can be genetic, based on defects of respiratory enzyme complexes or on the basis of the clinical syndromes. Due to the extremely variable clinical presentations of these disorders, a complete clinical and laboratory workup involving strict diagnostic criteria is essential.     

The syndromology of anorectal malformation (atresia,stenosis, ectopia)

The syndromes, associations, and developmental field defects that include anorectal dysgenesis (atresia, stenosis, ectopia) as a principal or facultative sign are discussed. Most of these disorders are identifiable by their genetic or teratogenic etiology, their distinctive phenotype, or both. Their precise diagnosis is crucial for estimation of recurrence risk and other aspects of reproductive counseling, and it is essential for classificatory progress. The “VACTERL association” should not be used to label a patient with anorectal malformation and other anomalies except by exclusion; this rule is particularly relevant when the patient lacks tracheoesophageal malformation. The degree (or variety) of anorectal malformation that occurs in a given pattern of multiple congenital anomalies may be inconstant. Furthermore, anorectal malformation may be a solitary expression of a familial syndrome.     

The syndromology of anorectal malformation (atresia, stenosis, ectopia).

The syndromes, associations, and developmental field defects that include anorectal dysgenesis (atresia, stenosis, ectopia) as a principal or facultative sign are discussed. Most of these disorders are identifiable by their genetic or teratogenic etiology, their distinctive phenotype, or both. Their precise diagnosis is crucial for estimation of recurrence risk and other aspects of reproductive counseling, and it is essential for classificatory progress. The "VACTERL association" should not be used to label a patient with anorectal malformation and other anomalies except by exclusion; this rule is particularly relevant when the patient lacks tracheoesophageal malformation. The degree (or variety) of anorectal malformation that occurs in a given pattern of multiple congenital anomalies may be inconstant. Furthermore, anorectal malformation may be a solitary expression of a familial syndrome.     

The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes

In a subgroup of patients with neuromyelitis optica (NMO), a severe inflammatory demyelinating disorder of autoimmune origin characterized by recurrent attacks of optic neuritis and longitudinally extensive transverse myelitis, a parainfectious pathogenesis may play a central role. We systematically evaluated such reports in the literature published between 1975 and 2009 in order to characterize parainfectious NMO syndromes. Identified were 25 cases, whereof 11 were in association with viral and 14 with bacterial pathogens. Sufficient clinical and paraclinical information was available in 16 patients (11 women). Median age was 8 years for children and 32 years for adults. Acute febrile illness preceding or in close relation with neurological symptoms was most common and the association with varicella-zoster virus and Mycobacterium pneumonia most frequent. In the majority, the course was monophasic (88%) and disability sustained (with complete recovery in only 25%). Seven patients fulfilled the revised NMO diagnosis criteria of 2006; none was seropositve for aquaporin-4 antibodies. Immune mechanisms potentially involved in parainfectious NMO syndromes include bystander activation, molecular mimicry, and the exacerbation of a pre-existing central nervous system (CNS) disorder by a systemic infection. However, current studies are not sufficient to define the place of parainfectious NMO syndromes within the spectrum of inflammatory disorders of the CNS.