Congenital Neuropathy Research Articles

Congenital Axonal Neuropathy and Encephalopathy

Congenital axonal neuropathy associated with encephalopathy appears to be very rare. Only a few cases have been reported in the literature. In the last 25 years, we have seen seven patients affected by congenital axonal neuropathy with encephalopathy. Biopsies of their sural nerves revealed axonal atrophy and loss of large-diameter nerve fibers. All of these patients presented at birth or soon thereafter with hypotonia associated with distal weakness and diffuse areflexia. Central nervous system manifestations included microcephaly, seizures, and developmental delay. Outcomes were poor. Four children died before age 3 years from respiratory insufficiency or aspiration pneumonia. The three surviving patients manifested severe developmental delay. In our most recent patient, Western-blot analysis of snap-frozen specimens of the temporal and cerebellar cortex demonstrated an absence or marked decrease of microtubule-associated protein types 1A and 2, compared with age-matched control subjects. Calloso-splenial hypogenesis and neurofilament swellings were also documented in the deep white matter and adjacent cortex. The absence or hypo-expression of central nervous system microtubule-associated proteins has never been reported in congenital neuropathies, and may represent a new clinicopathologic entity.

Small heat shock protein Hsp27 is required for proper heart tube formation

The small heat shock protein Hsp27 has been shown to be involved in a diverse array of cellular processes, including cellular stress response, protein chaperone activity, regulation of cellular glutathione levels, apoptotic signaling, and regulation of actin polymerization and stability. Furthermore, mutation within Hsp27 has been associated with the human congenital neuropathy Charcot-Marie Tooth (CMT) disease. Hsp27 is known to be expressed in developing embryonic tissues; however, little has been done to determine the endogenous requirement for Hsp27 in developing embryos. In this study, we show that depletion of XHSP27 protein results in a failure of cardiac progenitor fusion resulting in cardia bifida. Furthermore, we demonstrate a concomitant disorganization of actin filament organization and defects in myofibril assembly. Moreover, these defects are not associated with alterations in specification or differentiation. We have thus demonstrated a critical requirement for XHSP27 in developing cardiac and skeletal muscle tissues.

IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination

The gene affected in the congenital neuropathy familial dysautonomia (FD) is IKBKAP that codes for the IKAP/hELP1 protein. Several different functions have been suggested for this protein, but none of them have been verified in vivo or shown to have some link with the FD phenotype. In an attempt to elucidate the involvement of IKAP/hELP1 in brain function, we searched for IKAP/hELP1 target genes associated with neuronal function. In a microarray expression analysis using RNA extracted from the cerebrum of two FD patients as well as sex and age matched controls, no genes were found to be upregulated in the FD cerebrum. However, 25 genes were downregulated more than 2-fold in the cerebrum of both the male FD child and female FD mature woman. Thirteen of them are known to be involved in oligodendrocyte development and myelin formation. The down regulation of all these genes was verified by real-time PCR. Four of these genes were also confirmed to be downregulated at the protein level. These results are statistically significant and have high biological relevance, since seven of the downregulated genes in the cerebrum of the FD patients were shown by others to be upregulated during oligodendrocyte differentiation in vitro. Our results therefore suggest that IKAP/hELP1 may play a role in oligodendrocyte differentiation and/or myelin formation.

Bilateral Congenital Trigeminal Sensorimotor Neuropathy Presents as a Severe Open-Bite Malocclusion

Trigeminal neuropathy is commonly seen as a disorder of sensation in the distribution of the fifth cranial nerve. An 18-year-old girl was referred to our hospital because of a severe anterior open-bite deformity with a long face after presurgical orthodontic treatment. Surgical plan was maxillary posterior impaction with anterior advancement, mandibular setback operation, and genioplasty with vertical chin reduction in one stage. One month after surgery she had still difficulty closing her mouth. With the help of her hands, she could close her mouth fully on normocclusion. Weakness of the jaw-closing muscles was confirmed with muscle testing. She had impaired sensation to light touch and pinprick in the distribution of the maxillary and mandibular divisions of the bilateral trigeminal nerves. T1-weighed MRI of the brain showed bilaterally atrophy of the muscles innervated by the trigeminal motor nerve (i.e., the masseter, medial and lateral pterygoids, and temporalis muscles). We thoroughly evaluated our patient through history and clinical, laboratory, electrophysiological, and radiological examinations. The motor and the sensory V2 and V3 branches of the trigeminal nerve were congenitally damaged. As far as we know, this case is the first bilateral congenital trigeminal sensorimotor neuropathy presented with maxillo-mandibular and a severe open-bite deformity.

Molecular Basis of Hirschsprung’s Disease and Other Congenital Enteric Neuropathies

The enteric nervous system (ENS) is a complex neural network that controls many essential functions in the gastrointestinal tract, including the regulation of intestinal peristalsis. Neural crest cells migrate, proliferate, and differentiate within the intestinal wall to give rise to the neurons and glial cells of the ENS. Failure of this process to occur normally during embryogenesis can lead to severe disorders of intestinal motility, the most common of which is Hirschsprung's disease. Several proteins have been identified as being essential for normal ENS development, including members of the Ret and endothelin-3 signaling pathways. The analysis of transgenic mice harboring mutations in these critical genes has greatly enhanced our understanding of the molecular regulation of ENS development and of the etiology of intestinal aganglionosis. Building on this fundamental research, much has been learned recently about the genetics underlying the complex inheritance pattern of Hirschsprung's disease. Continued progress in elucidating the molecular basis of normal and abnormal ENS development will greatly enhance our understanding of congenital enteric neuropathies and improve our ability to diagnose and treat children affected by these disabling conditions.

Obstetrical and Pediatric Anesthesia Anesthetic management of children with Moebius sequence

Moebius sequence is a rare congenital absence of the sixth and seventh cranial nerves, although there may be additional congenital cranial neuropathies. Developmental delay, cardiac and musculoskeletal abnormalities may also co-exist. Oro-facial manifestations include bilateral facial nerve palsy resulting in a mask like facies, drooling, incomplete eye closure, and strabismus secondary to the extra-ocular muscle imbalance. This condition has multiple implications for anesthetic care.We reviewed 111 anesthesia records of 46 patients with Moebius sequence for anesthesia technique and related complications.Facial nerve palsy was universally present and bilateral in 44 (93.6%) patients. Thirty-two (68%) had concomitant sixth nerve palsy. Oro-facial and limb abnormalities were present in 16 (35%) and 18 (39%) of patients respectively. Endotracheal intubation, when attempted, was easy in 76 of 106 cases. Tracheal intubation was consistently difficult in seven patients and intubation failure occurred in a single patient only. Statistically significant factors associated with difficult tracheal intubation included structural abnormalities of the mandible and palate and abnormalities of four cranial nerves (IX, X, XI, XII).We confirm that tracheal intubation may be difficult in patients with Moebius sequence. We identify disease features that might predict a difficult tracheal intubation and thus allow the anesthesiologist an opportunity to plan accordingly.

Cardiofaciocutaneous syndrome (CFC) with congenital peripheral neuropathy and nonorganic malnutrition: An autopsy study

Many phenotypic manifestations have been reported in cardiofaciocutaneous (CFC) syndrome, but none, to date, are pathognomonic or obligatory. Previous histopathological studies reported findings in skin and hair; no autopsy studies have been published. We report the clinical and autopsy findings of a 7-year-old boy with severe CFC syndrome and malnutrition of psychosocial origin. Manifestations of CFC, reported previously, included macrocephaly and macrosomia at birth; short stature; hypotonia; global developmental delays; dry, sparse thin curly hair; sparse eyebrows and eyelashes; dilated cerebral ventricles; high cranial vault; bitemporal constriction; supraorbital ridge hypoplasia; hypertelorism; ptosis; exophthalmos; depressed nasal bridge; anteverted nostrils; low-set, posteriorly-rotated, large, thick ears; decayed, dysplastic teeth; strabismus; hyperelastic skin; wrinkled palms; keratosis pilaris atrophicans faciei; ulerythema ophryogenes; hyperkeratosis; gastroesophageal reflux; and tracheobronchomalacia. Additional findings, not previously reported, include islet cell hyperplasia, lymphoid depletion, thymic atrophy and congenital hypertrophy of peripheral nerves with onion bulb formations. Although the islet cell hyperplasia, lymphoid depletion, and thymic atrophy are nonspecific findings that may be associated with either CFC or malnutrition, the onion bulb hypertrophy is specific for a demyelinating-remyelinating neuropathy. These findings implicate congenital peripheral neuropathy in the pathogenesis of the developmental delays, feeding difficulties, respiratory difficulties, ptosis and short stature in this case. Additional studies of other cases of CFC are needed.

Type I Spinal Muscular Atrophy Can Mimic Sensory-Motor Axonal Neuropathy

Spinal muscular atrophy is a group of allelic autosomal recessive disorders characterized by progressive motoneuron loss, symmetric weakness, and skeletal muscle atrophy. It is traditionally considered a pure lower motoneuron disorder, for which a current definitive diagnosis is now possible by molecular genetic testing. We report two newborns with a clinical phenotype consistent with that of spinal muscular atrophy type I and nerve conduction studies and electromyography suggesting more extensive sensory involvement than classically described with spinal muscular atrophy. Molecular testing confirmed spinal muscular atrophy in patient 1 but not in patient 2. Thus, in the setting of a suspected congenital axonal neuropathy, molecular testing might be necessary to distinguish spinal muscular atrophy type I from infantile polyneuropathy.

Episodic somnolence in an infant with Riley-Day syndrome

Familial dysautonomia is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population and has rarely been diagnosed in the neonatal period in unaffected families. This report describes a patient who, during the neonatal period, had episodes of marked decrease in the level of consciousness with durations of 4-15 hours. Other signs and symptoms included the absence of fungiform papillae of the tongue, areflexia, and failure to thrive. The diagnosis was confirmed by the demonstration of mutations in the IkappaB kinase complex-associated protein gene with the identification of IVS20 (+6T --> C) which is responsible for more than 99.5% of known Ashkenazi Jewish patients with familial dysautonomia. The prognosis of this disease and the possibility of genetic counseling are clearly related with an early definitive diagnosis, and this patient illustrates the importance of episodes of somnolence as a possible sign of familial dysautonomia.

A new form of congenital proprioceptive sensory neuropathy associated with arthrogryposis multiplex

We report two siblings who presented with non-progressive marked sensory ataxia associated with arthrogryposis multiplex congenita (AMC). Deep tendon reflexes and H reflex were completely absent, but F waves were preserved. The sensory nerve conduction studies indicated the presence of relatively mild sensory polyneuropathy. The conventional somatosensory evoked potentials (SEPs) showed mildly prolonged latency for both the peripheral and cortical responses, suggesting a slowed conduction through the peripheral as well as central pathway. However, the 'proprioceptive SEPs' were absent, in conformity with complete loss of joint sense. Sural nerve biopsy revealed only mild thinning of myelin in the younger sister but was entirely normal in her brother. Taken together with the characteristic electrophysiological findings, the symptoms were considered to be due to predominant involvement of a selective population of somatosensory ganglions. The present cases showed no progression of the neurological deficit what-so-ever since birth, which strongly suggests a developmental anomaly or aplasia of a limited population of peripheral sensory neurons.

‘Congenital peripheral neuropathy presenting as apnoea and respiratory insufficiency: spinal muscular atrophy with respiratory distress type 1 (SMARD1)’

‘Congenital peripheral neuropathy presenting as apnoea and respiratory insufficiency: spinal muscular atrophy with respiratory distress type 1 (SMARD1)’

Congenital peripheral neuropathy with optic atrophy and symmetric white matter lesions

Objective: Peripheral neuropathy with optic atrophy is a clinically and genetically heterogeneous group of disorders classified as hereditary motor and sensory neuropathy (HMSN) Type VI. We report on a case which shows not only peripheral but also central myelinisation defects.

Autologous muscle transfer for reconstruction of the lower urinary tract.

The recent experimental results of using functioning muscle transfer to the bladder have been shown to be useful for some clinical indications. LDDM proved to be a viable option for the treatment of patients with an acontractile bladder due to traumatic or congenital lower motor neuropathy. A logical development for complete bladder substitution would be to combine the well-vascularized and contractile latissimus dorsi muscle transplant with cultivated and expanded autologous urothelial cells. A scaffolding, such as bioabsorbable polymer, alginate, or small intestinal sumucosa, may be useful to convey the in vitro-created urothelial layer onto the muscle and to avoid osteogenesis. Experimental studies are necessary, however, to rule out whether these materials induce fibrosis, leading to stiffness of the neobladder wall, and thereby reducing contractile function and voiding capability of the transferred muscle.

Familial incidence of urinary incontinence

Objective: The purpose of this study was to evaluate whether urinary incontinence is more common in family members of women with incontinence compared with continent individuals. Study Design: Women who were examined at 2 different outpatient facilities over a 2-year period received a questionnaire that covered social, behavioral, and medical issues. They were also asked whether they had a family member who complained of urinary incontinence and, if so, the degree of the relationship. Subjects were excluded for the following reasons: not mentally competent, difficulty understanding the written English language, and a history of bladder cancer or of acquired or congenital neuropathy. Statistical analyses were conducted with chi-squared tests for differences between groups; a probability of <.05 was defined as significant. Results: A total of 833 women received the questionnaire; 667 women answered the question about urinary incontinence in family members. These 667 women were divided into 3 groups: group I, 441 incontinent women from the first facility; group II, 112 continent women from the first facility; and group III, 114 continent women from the second facility. Women with at least 1 relative with urinary incontinence were 34.9% in group I, 16.1% in group II, and 5.3% in group III. This difference was statistically significant. In a comparison of group I and group II, the odds that an incontinent woman had at least 1 relative with incontinence were 2.6 times higher (95% CI, 1.50-4.48); comparing group I and group III, the odds were 9.6 times higher (95% CI, 4.17-22.25). Conclusion: In our study population, women with urinary incontinence were more likely to have at least 1 family member also with incontinence when compared with women who were continent. (Am J Obstet Gynecol 2002;187:53-5.)

Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews.

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish (AJ) population. Mutations in the IkappaB kinase complex-associated protein (IKBKAP) gene cause FD. Two IKBKAP mutations, IVS20(+6T --> C) and R696P, have been identified in FD patients of AJ descent. The splice site mutation IVS20(+6T --> C) is responsible for > 99.5% of known AJ patients with FD, and haplotype analyses were consistent with a common founder. In contrast, the R696P mutation has been identified in only a few AJ patients. To facilitate carrier detection, a single PCR and allele-specific oligonucleotide (ASO) hybridization assay was developed to facilitate the detection of both the IVS20(+6T --> C) and R696P mutations. Screening of 2,518 anonymous AJ individuals from the New York metropolitan area revealed a carrier frequency for IVS20(+6T --> C) of 1 in 32 (3.2%; 95% CI, 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P lesion, indicating that the mutation was rare in this population (< 1 in 2,500). This sensitive and specific assay should facilitate carrier screening for FD mutations in the AJ community, as well as postnatal diagnostic testing.

Muscle CT in peripheral neuropathies.

We studied retrospectively the muscle CT scans of 60 acquired and 40 congenital motor peripheral neuropathies in order to define the diagnostic usefulness of muscle CT in these disorders. Fifty-five percent of the acquired and 72% of the congenital forms showed muscle CT pathological changes correlated to the clinical severity. The typical finding was pure muscle atrophy but several patients also revealed areas of hypodensity. In most of the acquired forms, muscle changes affected both the thighs and legs with a prevalent involvement of the posterior muscles. The congenital forms showed early involvement of the anterior leg muscles. Our study suggests that a CT scan might be useful in evaluating the severity of muscular atrophy, its evolution in time and the prognosis of motor function, in confirming the diagnosis of acquired or congenital neuropathies, and in some cases in defining the phenotypes of congenital forms.

Myelinated Nerve Fibers In Glabrous Digital Skin

In the last decade, applying multiple immunolabeling with highly specific antibodies and confocal microscopy to skin biopsies, it has been possible to study extensively cutaneous innervation. This technique has proved to be reliable and even more sensitive than sural nerve biopsy to investigate mild dying back neuropathies with only a very distal involvement of nerve fibers. So far it has been used mainly on hairy skin to evaluate small fiber anomalies in congenital, acquired and idiopathic sensory neuropathies. Compared to hairy skin, glabrous skin has a peculiar characteristic: it is rich in mechanoreceptors and myelinated Aβ fibers. To study these structures we selected a group of healthy volunteers and recruited a group of patients affected by hereditary or acquired sensory neuropathies. Skin biopsy was performed using a three mm disposable punch in all subjects on fingertip. We stained the cutaneous samples with a panel of antibodies identifying different neural structures such as the axon, the myelin sheath, the Schwann cell, and the Meissner corpuscle capsula. Three‐D digitized images were acquired using a confocal microscope. We studied Meissner and intrapapillar myelinated nerve fiber density and using a dedicated software we measured in normal and neuropathic subjects area and density of innervation of Meissner corpuscles and thickness, internodal and Ranvier node length of the sensory fibers approaching the mechanoreceptors.

Congenital neuropathy with the absence of large myelinated fibers

Twelve patients with hereditary motor and sensory neuropathy with the absence of large myelinated fibers have been reported. All of these patients had central nervous system involvement. In this report, we describe the first patient with pure motor and sensory neuropathy with the absence of large myelinated fibers without central nervous system involvement. Morphometric analysis of the biopsied sural nerve specimen revealed extremely small myelinated fibers compared with previously reported patients. It is supposed that the cause of this disease might be the abnormal development of axons of the peripheral nerves.

Deletions in the spinal muscular atrophy gene region in a newborn with neuropathy and extreme generalized muscular weakness

A newborn presented with respiratory insufficiency requiring artificial ventilation, inability to swallow, lack of spontaneous movements including the facial muscles, and areflexia. Nerve conduction velocities were not recordable. Molecular analysis showed a homozygous deletion in the spinal muscular atrophy (SMN) gene region on chromosome 5q. Pathological and neuropathological examination revealed a normal of anterior horn cells, hypomyelinated axons in peripheral nerves and some atrophy of skeletal muscle fibres in combination with sarcoplasmic glycogen accumulation. This observation illustrates that severe congenital neuropathy can result from deletions in the SM gene.

Neurogenic bladder dysfunction.

Urodynamics are still essential for diagnosis and prognosis of neurogenic lower urinary tract-dysfunction and can not be replaced by other means of investigation so far, neither by a thorough clinical investigation nor by sophisticated means like magnetic resonance imaging. The findings with clinical investigations are specific, but not sensitive enough, and the spinal cord lesions may sometimes be beyond the resolution of magnetic resonance-scanning. Pharmacotherapy is still the corner stone in the management of detrusor hyperreflexia. Further studies with tolterodine, oxybutynin, trospiumchloride and propiverine have increased our knowledge about these substances. Capsaicin was proved to be the effective substance and not the alcoholic solution, which serves as a carrier. Intrathecal clonidine may represent a new conservative reversible alternative treatment for detrusor hyperreflexia. Experiments with detrusor strips from end-stage MMC-patients may explain the relative resistance of the low compliant bladder to the common anticholinergic/spasmolytic therapy. The differential indication for bladder augmentation, either using segments of the gastrointestinal-tract or performing a partial detrusor myectomy is ongoing, favourable results are reported for both techniques. Sacral posterior root rhizotomy is able to abolish detrusor hyperreflexia and therefore recommended for tetra- and paraplegics, however autonomic dysreflexia, if present, can not be totally abolished. Collagen injections for neuropathic sphincter incompetence can not be recommended as demonstrated in children with congenital neuropathy, a new design of an artificial sphincter must stand the test of time.