HSP109-III1 NCS Nerve Distal latency (ms) Amplitude mV for motor , µV for sensory) Velocity (m/s) Tibial (AHB) 5.2 3.2 mV 37 DPN (EDB) 4.5 2.5 mV 36 Median (APB) 4.1 5.2 mV 42 Ulnar (ADM) 3.4 6.1 mV 43 Median 3.5 µV 39 Ulnar 3.1 µV 39 Sural 4.0 µV 33 EMG Muscle Insertional activity Fibrillation Fasciculation Recruitment Duration/Amplitude Activation

Background and objective: Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. Methods: Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. Results: Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). Conclusion: It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype–phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.

A 38-year-old female, born to a consanguineous marriage, with a 2-year history of neuropsychiatric symptoms and mental decline, referred to our center for further assessments. On admission, she was bedridden and unable to talk and obey orders. She had severe rigidity and spasticity of extremities with brisk muscle stretch reflexes and bilateral Babinskie sign. She also had jerky movements of the limbs, consistent with myoclonus. Ophthalmological examination revealed neither optic atrophy nor retinopathy. MRI of the brain showed symmetric and extensive iron deposition in bilateral caudates, putamens, globus pallidi (GP), and SN (Fig. 1). Whole-exome sequencing revealed a homozygous mutation in the C19orf12 gene (NM_001031726.3: c.32C>T (p.Thr11Met), indicative of a diagnosis of mitochondrial membrane proteinassociated neurodegeneration (MPAN). MPAN is a subtype of neurodegeneration with brain iron accumulation syndromes caused by mutation in the C19orf12 gene. Clinically, MPAN presents with progressive spasticity, dystonia-parkinsonism, optic atrophy, motor neuronopathy, and neuropsychiatric and cognitive symptoms. 1 Although iron deposition in the SN and GP are typical of MPAN, there is one other case report of MPAN with iron deposition in the putamen and caudate nuclei. 2 This case is 1 of 2 cases with the oldest onset age reported so far in MPAN and suggests that p.Thr11Met mutation in the C19orf12 gene may cause a late-onset form of the disease with a rapidly progressive course and extensive iron deposition in the brain.

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Background: Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN (gigaxonin) gene. Herein, we reported the clinical presentations and results of genetic analysis of the first Iranian GAN case. Methods: Phenotypic data were obtained by neurologic examination, brain magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), and sonography from the proband. Deoxyribonucleic acid (DNA) was isolated from peripheral blood leucocytes and whole exome sequencing (WES) was performed. The candidate variant was screened by Sanger sequencing in the proband and her family members. Results: The proband was a 7-year-old girl who was admitted with a chief complaint of ataxia, muscle weakness, delayed developmental milestones, and history of psychiatric disorders. She was very moody and had clumsy gait, decreased deep tendon reflexes (DTRs) of lower limbs, and kinky hair. The brain MRI revealed white matter abnormality. The EMG revealed that her disease was compatible with the chronic axonal type of sensorimotor polyneuropathy; however, her EEG was normal. Results of the WES revealed a homozygous variant; c.G778T:p.E260* in the GAN gene, indicating the GAN disorder. Conclusion: The present study affirmed GAN allelic heterogeneity and resulted in the expansion of the phenotypic spectrum of GAN pathogenic variants. Identification of more families with mutations in GAN gene helps to further understand the molecular basis of the disease and provides an opportunity for genetic counseling especially in the populations with a high degree of consanguineous marriage such as the Iranian population.