Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Background: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features.Objective: To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design: Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Setting: Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. Patients: One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures: Results of genetic analyses and phenotypic observations.

Neuropathologic abnormalities can be sufficiently characteristic to suggest the genetic basis of some hereditary neuropathies such as those associated with mutations in MPZ, GJB1, GDAP1, MTMR2, SH3TC2, PRX, FGD4, and LMNA. We analyzed the morphologic features of 9 sural nerve biopsies from 6 patients with mutations of mitofusin 2. All patients presented in early childhood with axonal neuropathies designated as mild or severe motor and sensory neuropathy. In all cases, there was a marked decrease in density of myelinated fibers, mainly of large diameter fibers. These changes were more marked in the second biopsies of 3 patients that were performed from 7 to 19 years after the first biopsies. Neurophysiologic findings were most suggestive of axonal degeneration, but some onion bulbs were present in all cases. Axonal mitochondria were smaller than normal, were round, and were abnormally aggregated. These changes may result from abnormal mitochondrial fusion and fission. The results suggest that these clinical and pathological features may be sufficiently characteristic to suggest the diagnosis of mitofusin 2-related neuropathy.

We suggest a modification of the current classification and explain why such a change is needed.

Neonatal primary hyperparathyroidism (NPHT) is associated with an inactivating homozygous mutation of the calcium sensing receptor (CaSR). The CaSR is expressed most abundantly in the parathyroid glands and the kidney and regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption. NPHT leads to life threatening hypercalcemia, nephrocalcinosis, bone demineralization, and neurologic disabilities. Surgery is the treatment of choice. While waiting for surgery, bisphosphonates offer a good alternative to deal with hypercalcemia. Cinacalcet is a class II calcimimetic that increases CaSR affinity for calcium, leading to parathormone suppression and increased calcium renal excretion. At present, there is little evidence as to whether cinacalcet could improve the function of mutant CaSR in NPHT. We report a case of NPHT, treated successfully with bisphosphonates and cinacalcet after surgery failure. To our knowledge, it is the first time cinacalcet has been used for NPHT.