Amyotrophic lateral sclerosis with ragged-red fibers

BACKGROUND: Motor neuron diseases (amyotrophic lateral sclerosis [ALS] and spinal muscular atrophy [SMA]) have been rarely associated with mitochondrial respiratory chain defects. OBJECTIVES: To describe a patient with typical ALS and the finding of ragged-red fibers in muscle biopsy specimens and to review the literature on respiratory chain defects in ALS and SMA. DESIGN: Case report and review of the literature. SETTING: Collaboration between tertiary care academic hospitals. PATIENT: A 65-year-old man with typical ALS. MAIN OUTCOME MEASURES: The patient had 10% ragged-red fibers and 3% cytochrome-c oxidase-negative fibers in muscle biopsy specimens but no biochemical defects of respiratory chain enzymes or alterations of mitochondrial DNA (mtDNA). RESULTS: Amyotrophic lateral sclerosis with ragged-red fibers has been reported in 5 families and is associated with mtDNA mutations in some subjects. Spinal muscular atrophy without mutations in the survival motor neuron gene (SMN; OMIM 600354) has been associated with mtDNA depletion or with mutations in the cytochrome-c oxidase assembly gene (SCO2; OMIM 604377). CONCLUSION: Respiratory chain defects can mimic ALS or SMA and should be considered in the differential diagnosis.     

Juvenile Alpers disease

BACKGROUND: Alpers disease is commonly associated with polymerase gamma deficiency and usually affects infants or young children. OBJECTIVE: To report a juvenile case of Alpers disease due to mutations in the polymerase gamma gene (POLG1). DESIGN: Clinical, pathologic, biochemical, and molecular analysis. SETTING: Tertiary care university hospital and academic institutions. PATIENT: A 17-year-old adolescent girl with intractable epilepsy and liver disease. MAIN OUTCOME MEASURES: Clinical course and pathologic, biochemical, and molecular features. RESULTS: Biochemical and pathologic evidence suggested a respiratory chain defect, which was confirmed by enzyme analysis of the liver. Mutational analysis of POLG1 showed 2 novel mutations: T851A and R1047W. CONCLUSION: The POLG1 mutations can cause juvenile and childhood Alpers disease.     

Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1

OBJECTIVE: To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase gamma (POLG2) and a mutation in the OPA1 gene. DESIGN: Clinical examination and morphological, biochemical, and molecular analyses. SETTING: Tertiary care university hospitals and molecular genetics and scientific computing laboratory. PATIENT: A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal. RESULTS: A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase gamma gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). CONCLUSION: Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.     

Autonomic nervous system abnormalities in spinocerebellar ataxia type 2: a cardiovascular neurophysiologic study

Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables.     

Hyperhomocysteinemia and retinal vascular changes in patients with epilepsy

The possible occurrence of asymptomatic retinal vascular damage was investigated in 87 hyperhomocysteinemic (plasma total homocysteine >13mumol/L) adult epileptic patients (46 M, 41 F; age 34.2+/-7.5 years; mean plasma homocysteine levels 29.8+/-15.4mumol/L; duration of epilepsy 11.5+/-2.4 years) with no other risk factors for atherosclerosis. Plasma total homocysteine (t-Hcy) levels were assayed by high performance liquid chromatography. Retina vascular status was assessed by fundus oculi ophthalmoscopy performed in blind conditions by two skilled ophthalmologists and compared with that obtained from 102 randomly chosen epileptic patients and 94 healthy subjects, matched for age and sex, showing normal t-Hcy levels. No retina abnormality was detected in any of the subjects belonging to the three groups. Based on these results, we conclude that epileptic patients with mild to intermediate hyperhomocysteinemia are not at risk to develop retinal vascular disease.     

Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients

Objective

To evaluate the outcome of peniscopically controlled laser excision of early-stage penile carcinoma.

Methods

Patients treated from 1982 to 2006 were investigated. The primary treatment was excisional surgery alone for in situ or initially invasive flat tumors, and reductive chemotherapy followed by surgery for the exophytic lesions. All excisional procedures were conducted by CO₂ laser under peniscopic control.

Results

Of a total of 224 patients, 111 underwent partial excision of the glans and/or coronal sulcus surface, and 113 total surface excision. Forty patients underwent reductive chemotherapy. Complete excision was obtained in 221 cases (98.7%) at lateral margins and in 217 cases (96.9%) at deep margin. Postoperative complications were negligible. Overall, the 10-yr recurrence rate was 17.5% (95% confidence interval, 16.4–18.6%), and apparently was not affected by the in situ or invasive nature of the lesion. Amputation was required in nine patients, for a 10-yr amputation rate of 5.5% (range, 5.2–5.7%). In the remaining cases, organ form and curvature were preserved, with satisfactory cosmetic and functional results.

Conclusions

Early-stage penile carcinomas can be effectively treated with the organ-sparing strategy described here. Because local recurrences occur in a minority of patients and can be safely treated, organ preservation is compatible with local disease control. Reductive systemic chemotherapy in selected exophytic cases broadens the indication for our conservative approach.     

Combined internal uncusectomy and decompressive craniectomy for the treatment of severe closed head injury: experience with 80 cases

OBJECTIVES: Transtentorial brain herniation is a major cause of morbidity and death following severe closed head injury. The purpose of this study was to evaluate the efficacy of selective uncoparahippocampectomy and tentorial splitting as an adjuvant method of treating otherwise uncontrollable elevated intracranial pressure (ICP) while attempting to prevent or minimize the devastating consequences caused by transtentorial herniation. METHODS: The authors retrospectively reviewed data from a series of 80 consecutive cases of severe closed head injury (Glasgow Coma Scale [GCS] score < 8) treated in their neurosurgical unit. All patients had elevated ICP and downward tentorial herniation, as documented with ICP monitoring, and clinical examination and computed tomography, respectively. Given the evidence of acute and ongoing neurological deterioration, all patients were treated with selective uncoparahippocampectomy and tentorial edge incision followed by wide decompressive craniectomy and duraplasty. RESULTS: All injuries were caused by blunt trauma with signs of acute and/or progressive increased ICP causing downward transtentorial herniation. Fifty-eight patients were male and 22 were female with a mean age of 35 years and a mean preoperative GCS score of 5. Based on the current American Association of Neurological Surgeons guidelines for head trauma, an intraparenchymal ICP device (Camino, Integra) was placed in all patients who had a GCS score < 8, and ICP was consistently > 20 cm H2O. Whenever possible, risks and benefits were explained to family members, and then surgery was performed within 3-16 hours (median 6 hours). At a mean follow-up of 30 months, the outcome was favorable (Glasgow Outcome Scale [GOS] score of 4 or 5) in 60 patients (75%) and unfavorable (GOS score of 3) in 8 (10%), whereas the remaining 12 patients (15%) died at some point during the postoperative course. There was no survivor patient in a vegetative state. A younger age had a significant effect on positive outcome (p < 0.0005), as did an earlier operation (p < 0.04). The preoperative neurological status as assessed using the GCS as well as pupillary reactivity had no significant effect on outcome (p = 0.054 and p > 0.05, respectively). CONCLUSIONS: A selective uncoparahippocampectomy with a tentorial edge incision and a wide decompressive craniectomy with duraplasty can be an effective adjuvant form of aggressive treatment to improve outcome in patients with severe closed head injury, especially in those who are younger if they are treated promptly.     

Neurofibromatosis type 1 with external genitalia involvement presentation of 4 patients

Genitourinary neurofibromas with clitoral involvement in neurofibromatosis type 1 are rare, and even more infrequent are the neurofibromas involving genitalia in males. The most frequent presenting sign of neurofibroma in females is clitoromegaly with pseudopenis, and enlarged penis is the most common sign in males. Labium majus neurofibroma not associated with clitoral involvement is extremely rare. Magnetic resonance imaging demonstration of the neurofibromas has seldom been reported. We report 4 children, 3 girls and 1 boy, with plexiform neurofibromas involving the external genitalia. Three of the 4 patients had histologic confirmation of neurofibroma. Two girls with clitoral hypertrophy had a neurofibroma that infiltrated the clitoris and extended unilaterally to the lower bladder wall. One girl had a plexiform neurofibroma that affected a labium. One boy with asymmetric penile hypertrophy since 2 years of age and ipsilateral gluteal hypertrophy had plexiform neurofibromas that extended between the left lumbogluteal and penile regions, infiltrating the left rectum wall and bladder with compression of both structures, the left prostate, and the left half of the cavernous corpi with hypertrophy of this part and asymmetry of the penis. Magnetic resonance imaging demonstrated in all patients that external genitalia and plexiform neurofibroma formed images of nondetachable structures. However, hermaphroditism was discarded by chromosomal study in all 3 girls before ratifying the diagnosis of external genitalia neurofibroma.