Autonomic peripheral neuropathy

The autonomic neuropathies are a group of disorders in which the small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor, and pupillomotor systems, occur in varying combination in these disorders. Diabetes is the most common cause of autonomic neuropathy in more developed countries. Autonomic neuropathies can also occur as a result of amyloid deposition, after acute infection, as part of a paraneoplastic syndrome, and after exposure to neurotoxins including therapeutic drugs. Certain antibodies (eg, anti-Hu and those directed against neuronal nicotinic acetylcholine receptor) are associated with autonomic signs and symptoms. There are several familial autonomic neuropathies with autosomal dominant, autosomal recessive, or X-linked patterns of inheritance. Autonomic dysfunction can occur in association with specific infections. The availability of sensitive and reproducible measures of autonomic function has improved physicians' ability to diagnose these disorders.     

Hereditary dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a common and important cause of morbidity and mortality. Many factors can contribute to the development of this disorder, although most commonly the etiology is unexplained. However, recent studies in individuals with idiopathic DCM now reveal a heritable cause in 20–30% of individuals. Diverse modes of inheritance have been demonstrated, encompassing an autosomal dominant type (by far the most common), together with recessive and X-linked forms, and maternal inheritance through mitochondrial DNA. The hereditary forms of DCM (HDCM) predominantly affect the left ventricle, although inherited abnormalities affecting primarily the right ventricle also are described. HDCM may occur as a primary cardiomyopathy, or secondary to inherited systemic metabolic or neuromuscular disorders. The causative genes for primary HDCM of the autosomal dominant and recessive types have not yet been discovered, but the combination of family pedigree analysis and phenotyping by echocardiography, together with new genetic techniques, should now allow their identification. Knowledge of the gene or genes responsible for HDCM would improve diagnostic accuracy, facilitate genetic counseling, advance understanding of pathogenesis, and provide the starting point for new methods of treatment. Because of the frequently heritable nature of DCM, it is of great importance that a diligent search for all potentially affected family members be undertaken.     

Genetic counselling and prenatal diagnosis in disorders of the mitochondrial energy metabolism

Summary Point mutations in mitochondrial DNA, as found in MELAS, MERRF, NARP and other syndromes, are inherited via the maternal lineage. Genetic counselling can be beneficial, but prenatal diagnosis is not advantageous in these syndromes. Empirical data about the recurrence risk can be applied in Leber disease (LHON). Mitochondrial disorders not associated with a point mutation have a sporadic nature (large deletions/duplications in mitochondrial DNA) or are transmitted according to Mendelian laws. Autosomal dominant inheritance is likely to be found in disorders with depletion of mitochondrial DNA. X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E₁ subunit of the pyruvate dehydrogenase complex. Mutation analysis or linkage studies can be applied for carrier detection and prenatal diagnosis in these three types of mitochondriopathies. The majority of the disorders with a disturbed mitochondrial energy metabolism are likely inherited in an autosomal recessive mode. Prenatal diagnosis can be performed in the cases of cytochromec oxidase and NADH dehydrogenase deficiencies in chorionic villi in selected families.     

Achalasia of the Cardia Associated with Hereditary Cerebellar Ataxia

Achalasia of the cardia, a disorder associated with degenerative loss of esophageal myenteric ganglion cells, is reported in association with a recently described progressive neurological disorder, "early onset cerebellar ataxia with retained reflexes." This form of cerebellar ataxia is thought to be inherited as an autosomal recessive disorder. The occurrence of these two very rare neurodegenerative disorders in a single individual is of interest because of the potential genetic and pathogenetic implications of the association.     

Rare coagulation deficiencies

Deficiencies of coagulation factors (other than factor VIII and factor IX) that cause a bleeding disorder are inherited as autosomal recessive traits and are generally rare, with prevalences in the general population varying between 1 : 500 000 and 1 : 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations, because in these populations, consanguineous marriages are frequent. Owing to the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for haemophilia A and B. This article reviews these disorders in terms of their clinical manifestations and characterization of the molecular defects involved. The general principles of management are also discussed.Keywords: afibrinogenaemia, autosomal recessive disorders, factor VIII, factor XI, factor XIII.     

DL-2-amino-4-phosphonobutyric acid does not eliminate "ON" responses in the visual system of goldfish.

DL-2-Amino-4-phosphonobutyric acid (APB) suppresses activity in retinal ON pathways. It is generally assumed that loss of the ON pathway would result in loss of ON responses in the visual system. We tested this assumption by recording activity from the optic nerves of intact goldfish (Carassius auratus) before and after intraocular injection of APB. Whole-nerve responses to increments and decrements of light were compared to electroretinogram responses and to tectal evoked potentials. APB severely reduced the amplitude of the electroretinogram b-wave but left ON and OFF responses from the optic nerve and tectum intact, although decreased in sensitivity. We conclude that APB does not completely eliminate ON responses in the visual system, at least in goldfish. The selectivity and effectiveness of APB must be evaluated in other species before this agent can be relied upon as a useful tool in understanding the roles of ON and OFF pathways in visual function.     

Recessively inherited coagulation disorders

Deficiencies of coagulation factors other than factor VIII and factor IX that cause bleeding disorders are inherited as autosomal recessive traits and are rare, with prevalences in the general population varying between 1 in 500 000 and 1 in 2 million for the homozygous forms. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not as well established as for hemophilia A and B. We investigated more than 1000 patients with recessively inherited coagulation disorders from Italy and Iran, a country with a high rate of recessive diseases due to the custom of consanguineous marriages. Based upon this experience, this article reviews the genetic basis, prevalent clinical manifestations, and management of these disorders. The steps and actions necessary to improve the condition of these often neglected patients are outlined.     

Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors

The mature optic nerve cannot regenerate when injured, leaving victims of traumatic nerve damage or diseases such as glaucoma with irreversible visual losses. Recent studies have identified ways to stimulate retinal ganglion cells to regenerate axons part-way through the optic nerve, but it remains unknown whether mature axons can reenter the brain, navigate to appropriate target areas, or restore vision. We show here that with adequate stimulation, retinal ganglion cells are able to regenerate axons the full length of the visual pathway and on into the lateral geniculate nucleus, superior colliculus, and other visual centers. Regeneration partially restores the optomotor response, depth perception, and circadian photoentrainment, demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.     

Multineuronal codes in retinal signaling.

The visual world is presented to the brain through patterns of action potentials in the population of optic nerve fibers. Single-neuron recordings show that each retinal ganglion cell has a spatially restricted receptive field, a limited integration time, and a characteristic spectral sensitivity. Collectively, these response properties define the visual message conveyed by that neuron's action potentials. Since the size of the optic nerve is strictly constrained, one expects the retina to generate a highly efficient representation of the visual scene. By contrast, the receptive fields of nearby ganglion cells often overlap, suggesting great redundancy among the retinal output signals. Recent multineuron recordings may help resolve this paradox. They reveal concerted firing patterns among ganglion cells, in which small groups of nearby neurons fire synchronously with delays of only a few milliseconds. As there are many more such firing patterns than ganglion cells, such a distributed code might allow the retina to compress a large number of distinct visual messages into a small number of optic nerve fibers. This paper will review the evidence for a distributed coding scheme in the retinal output. The performance limits of such codes are analyzed with simple examples, illustrating that they allow a powerful trade-off between spatial and temporal resolution.     

Leber's hereditary opric neuropathy: a case report

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that primarily affects the optic nerve, causing bilateral vision loss in juveniles and young adults. A 12-year-old boy had complained of blurred vision in both eyes for more than 1 year. His best-corrected visual acuity was 0.08 in the right eye and 0.1 in the left. Ophthalmologic examination showed bilateral optic disc hyperemia and margin blurring, peripapillary telangiectasis, and a relative afferent pupil defect in his right eye. Fluorescein angiography showed no stain or leakage around the optic disc in the late phase. Visual field analysis showed central scotoma in the left eye and a near-total defect in the right. Upon examination of the patient's mitochondrial DNA, a point mutation at nucleotide position 11778 was found, and the diagnosis of LHON was confirmed. Coenzyme Q10 was used to treat the patient.     

Unusual presentation of multiple myeloma with unilateral visual loss and numb chin syndrome in a young adult

A 39-year-old man presented with unilateral visual loss as the first sign of multiple myeloma (MM). His visual loss was due to a plasmacytoma in the sphenoid sinus compressing the optic nerve with resultant optic nerve atrophy. Shortly after this presentation he developed numb chin syndrome due to a mandibular plasmocytoma compressing the mental nerve. His MM progressed rapidly despite treatment with high-dose steroids and alkylating agents and he required allogeneic bone marrow transplantation in order to achieve a remission. We reviewed the published medical literature on the presentation of MM with visual impairment and present a summary in tabular form in this paper. This is the first reported case of MM presenting with isolated complete visual loss due to intracranial extrinsic compression of the optic nerve since the advent of modern cross-sectional imaging. Multiple myeloma needs to be included in the differential diagnosis of cranial neuropathies and skull base neoplasms even in adults under 40 years of age.     

Peroral endoscopic myotomy in a pregnant woman diagnosed with mitochondrial disease: A case report

BACKGROUNDAchalasia is a primary esophageal motility disease characterized by impairment of normal esophageal peristalsis and absence of relaxation of the lower esophageal sphincter. Sometimes is can be a part of some genetic disorders. One of the causes of gastrointestinal motility disorders, including achalasia, is mitochondrial defects.CASE SUMMARYWe report about a pregnant woman with a history of symptoms associated with inherited mitochondrial disease, which was confirmed by genetic tests, and who was treated via peroral endoscopic myotomy.CONCLUSIONPeroral endoscopic myotomy is possible treatment option for a pregnant woman with achalasia caused by mitochondrial disease.     

Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy.

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, we propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.     

Malignant infantile osteopetrosis initially presenting with neonatal hypocalcemia: case report

Autosomal recessive "malignant" osteopetrosis is a rare congenital disorder relating to bone resorption abnormalities. It is believed to arise due to the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and, clinically, to the signs and symptoms of bone marrow failure. Impaired bone remodeling associated with dysregulated activity of osteoclasts for such a condition may typically result in bony narrowing of the cranial nerve foramina, which typically results in cranial nerve (especially optic nerve) compression. Abnormal remodeling of primary woven bone to lamellar bone results in "brittle" bone that is prone to fracture. Thus, fractures, visual impairment, and bone marrow failure are the classical features of this disease. We describe the case of a 23-day-old boy in whom neonatal hypocalcemia was present initially after birth. Malignant infantile osteopetrosis (MIO) was diagnosed for the patient at 4 months of age based on evidence of anemia, thrombocytopenia, leukoerythroblastosis, sclerotic bone, hepatosplenomegaly, and visual deficit from a bony encroachment by the cranial nerve foramina. Although only occasionally reported previously, MIO remains essentially unrecognized by clinicians as a cause of neonatal hypocalcemia, which often results in diagnostic confusion and delay. This is important in the context of curative hemopoietic stem cell transplantation where preservation of sight may depend upon early intervention.     

Impaired visual evoked potential and primary axonopathy of the optic nerve in the diabetic BB/W-rat

Summary The spontaneously diabetic BB/W-rat has emerged as an important model system for somatic and autonomic diabetic polyneuropathy. In this study we examined visual evoked potentials and the presence of morphometric and structural changes in the optic nerve and the retinal ganglion cells and their afferent axons contained in the retinal nerve fibre layer. A six-month duration of diabetes mellitus was associated with significant increases in the latencies of the visual evoked potentials. The latency of the first positive potential showed a 44% increase, and that of the first negative potential was prolonged by 41%. No significant changes were demonstrated at any of the amplitudes. In the optic nerve mean myelinated fibre size was significantly reduced to 82% of control values, which was accounted for by a significant reduction in axonal size. Axo-glial dysjunction, a prominent structural defect of diabetic somato-sensory neuropathy in both man and diabetic rodents, was non-significantly increased in the optic nerve. In diabetic animals retinal ganglion cells displayed dystrophic changes. No such changes were observed in age- and sex-matched control animals. Proximal axons of the retinal nerve fibre layer showed an increase in dystrophic axons in diabetic BB/W-rats. Morphometric analysis of optic nerve capillaries revealed no abnormalities except for basement membrane thickening. The present data suggest that the diabetic BB/W-rat develops a central sensory neuropathy, characterized functionally by prolonged latencies of the visual evoked potentials and structurally by an axonopathy of optic nerve fibres.This study was presented in part at the 3rd International Workshop on Lessons from Animal Diabetes, Tokyo, Japan, September, 1990     

Apparently dominant transmission of a recessive disease: deficiency of factor VII in Iranian Jews

In inherited disorders transmitted as autosomal recessive traits the children of affected individuals are usually asymptomatic and phenotypically normal because they are heterozygous for the defect. In an Iranian Jewish family with moderately severe deficiency of coagulation factor VII (an autosomal recessive bleeding disorder) the son of an affected woman was also affected. DNA analysis of the factor VII gene showed that this unusual situation was due to the fact that he inherited an abnormal allele with the Ala244Val missense mutation from both the homozygous mother and the heterozygous father. The parents, although not overtly consanguineous, belong to the same ethnic group of Iranian Jews, among whom this factor VII gene mutation reaches high frequencies (between 2 and 3%) in the heterozygous state.     

Genetics of Hypophosphatasia

Hypophosphatasia (HPP) results from mutations in the ALPL gene, mostly missense mutations. The gene is subject to a very high allelic heterogeneity, and some of these mutations have a dominant negative effect, two features that explain the most part of the clinical heterogeneity. Severe forms of the disease (perinatal and infantile) are inherited as an autosomal recessive trait. In the milder forms, autosomal recessive and autosomal dominant inheritance coexist. Experimental data show that there is a good correlation between the severity of the disease and in vitro alkaline phosphatase activity of the mutant protein. As a consequence of the existence of dominant mutations, moderate forms may be recessively or dominantly inherited and are expected more frequent than severe forms. The incidence of severe forms, inherited as a recessive trait, has been estimated at 1/300,000 in Europe. Genetic counseling is difficult in families where the mode of inheritance is unclear, or in prenatal context because of the prenatal benign form that may mimic severe perinatal HPP. During the ten last years, the mechanism of mineralization has been greatly deciphered, pointing out others gene that could modulate the HPP phenotype and explain particular cases where the phenotype does not correlate with the phenotype.     

Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation

Phosphorous is essential for multiple cellular functions and constitutes an important mineral in bone. Hypophosphatemia in children leads to rickets resulting in abnormal growth and often skeletal deformities. Among various causes of low serum phosphorous are inherited disorders associated with increased urinary excretion of phosphate, including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Recent genetic analyses and subsequent biochemical and animal studies have revealed several novel molecules that appear to play key roles in the regulation of renal phosphate handling. These include a protein with abundant expression in bone, fibroblast growth factor 23 (FGF23), which has proven to be a circulating hormone that inhibits tubular reabsorption of phosphate in the kidney. Two other bone-specific proteins, PHEX and dentin matrix protein 1 (DMP1), appear to be necessary for limiting the expression of fibroblast growth factor 23, thereby allowing sufficient renal conservation of phosphate. This review focuses on the clinical, biochemical, and genetic features of inherited hypophosphatemic disorders, and presents the current understanding of hormonal and molecular mechanisms that govern phosphorous homeostasis.     

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 μg/mL) were tested on 24 rats, and the higher dose was found to be more effective. Glaucoma was then induced in an additional 36 rats: half untreated and half treated with 200 μg/mL NGF QID for 7 weeks. Apoptosis/survival of RGCs was evaluated by histological, biochemical, and molecular analysis. Three patients with advanced glaucoma underwent psychofunctional and electrofunctional tests at baseline, after 3 months of NGF eye drops, and after 3 months of follow-up. Seven weeks of elevated IOP caused RGC degeneration resulting in 40% cell death. Significantly less RGC loss was observed with NGF treatment (2,530 ± 121 vs. 1,850 ± 156 RGCs/mm²) associated with inhibition of cell death by apoptosis. Patients treated with NGF demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity. NGF exerted neuroprotective effects, inhibiting apoptosis of RGCs in animals with glaucoma. In 3 patients with advanced glaucoma, treatment with topical NGF improved all parameters of visual function. These results may open therapeutic perspectives for glaucoma and other neurodegenerative diseases.