Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG 7 gene

Autosomal recessive hereditary spastic paraparesis is rare.We present 4 patients with slowly progressive predominantly lower limb spasticity and ataxia. Only one patient had family history of ataxia but without any underlying diagnosis. All of them proved negative for the mutation of Spinocerebelalr ataxia genes SCA 1,2,3 and 6. All had mutation in the SPG 7 gene suggestive of autosomal recessive hereditary spastic paraparesis. One of the heterozygous mutatnts showed a novel c1617delC, p(Val540fs) frameshift mutation in exon 12 of the SPG 7 gene. SPG7 mutation accounts for 1.5-7% of all the HSP but it is the cause of undiagnosed ataxia in 18.6% in a recent case series. SPG7 mutation should be remembered as an important cause of undiagnosed ataxia especially where next generation sequencing is not widely avaialbale or affordable.

T he spastic paraplegia 7 gene (SPG7) is located in the long (q) arm of chromosome 16 at position 24.3.Protein product of SPG 7 gene Paraplegin is involved in the maintenance of mitochondrial function by forming a part of the mitochondrial multimeric mAAA metaloprotease complex. 1,2 More than 77 different mutations of the SPG7 gene have been described in the literature so far. 3 Mutation is the SPG7 is responsible for autosomal recessive Hereditary Spastic Paraparesis (ARHSP). Though SPG7 mutation accounts for 1.5-7% of all the HSP but it is the cause of undiagnosed ataxia in 18.6% in a recent case series. 1,4 Spastic paraplegia 7 (SPG-7) can present as a pure and complex phenotype. 3,5 The complex phenotype shows clinical features like younger age of onset, optic nerve involvement, upper limb involvement, cognitive deficits and peripheral neuropathy in addition to features like pyramidal tract signs and ataxia seen in the pure phenotype of Spastic paraplegia. 5 Many patients with SPG 7 mutation present with subtle signs which can only be diagnosed with careful examination. 4 The mechanism of neuronal damage in SPG 7 mutation is not yet fully understood.
We described a cohort of 4 patients diagnosed as Autosomal Recessive HSP with a novel mutations of the SPG 7 gene. This mutation is an important cause of undiagnosed ataxia with significant risk of transmission to the future generations. We described not only a probably pathogenic noble SPG 7 gene mutation but also suggested to carefully search for ophthalmological signs like ptosis and ophthalmoparesis as they remain an important diagnostic clue for SPG 7 mutation testing.
Case Report. Patient information. All patients in our case series were Caucasian male between 32 to 47 years old when the symptoms started (Table 1). However one patient presented to us at the age of 70 years and another at 61 years of age. All of our patients presented with slowly progressive ataxia and 2 had fall on multiple occasions. Only one person had family history of undiagnosed ataxia. All of them were referred by either the GP or the peripheral hospitals as the cause of their symptoms were unclear.
Clinical findings. All of them demonstrated spasticity in the lower limbs. First three patients revealed some degree of horizontal ophthalmoplegia ( Table 1). The third patient had asymmetric ptosis in addition to ophthalmoplegia. All of them had signs of cerebellar ataxia.
Diagnostic information. All 4 patients were subject to routine bloods, B12, folate, thyroid function test, copper, nerve conduction studies, etc. Then all had routine genetic testing for ataxia including spinocerebellar ataxia, Friedreich's ataxia (Frataxin) Fragile X Associated Tremor/Ataxia syndrome (FRXTA) ( Table 2). They subsequently had next generation sequencing of 21 gene panel for hereditary spastic paraparesis.
The Magnetic resonance imaging (MRI) showed some degree of cerebellar atrophy in first three patients. However the last patient had significant pan-cerebellar atrophy in MRI scan ( Table 2). None of them showed any evidence of cord compression, demyelination or space occupying lesion in whole spine magnetic resonance imaging. The genetic screening for spinocerebellar ataxia (SCA 1,2,3 and 6) were negative for all. Patient 4 had additional testing for mutation in SCA 7 which turned out to be negative.
The next generation sequencing involving 21 genes in the spastic paraparesis panel revealed autosomal recessive hereditary spastic paraparesis due to the mutation in Spastic paraparesis 7 gene (SPG 7) in all of them with a novel mutation in one of them (Table 3). All these mutations were comfirmed by conventional Sanger sequencing.
Therapeutic intervention. All the patients were informed approximately their results and were sent for physiotherapy and occupational therapy assessment. The first 2 were also prescribed Baclofen for spasticity.
Follow up and outcomes. Subsequently during the follow up the first 2 patients complained that their balance worsened while the remaining 2 patients said that they were unchanged. The 2 young patients were referred for further genetic counselling as they were concerned about their children (Table 3). Discussion. All patients stated that they were struggling to cope with the symptoms but they were relieved to have a diagnosis though not treatable. First 2 pateints still work but mostly office jobs. In our series of 4 patients all had ataxia with 3 had ophthalmoplegia of variable degrees. One had a novel mutation (c1617delC ,p(Val540fs) in exon 12 (Figure 1). Since the mutation created a frameshift it is highly likely to be pathogenic though we could not study the full family. The variant pAla510 Val was the most common mutation in the SPG 7 gene (Figure 2). The common exons of the SPG 7 gene involved in the mutation process were 11 and 12. Out of the 77 different mutations of SPG7 gene that have been identified so far 9 were gross deletions.Warnecke T et al 6 4 This explains why ataxia and ophthalmoparesis (due to mitochondrial dysfunction) are common in SPG7 mutation. In    fact, our series shows that ophthalmological signs are important diagnostic clue for the SPG 7 genetic testing especially when the next generation sequencing not affordable or widely available. AAA metalloproteases of the inner mitochondrial membrane, paraplegin and AFG3L2, participate in the biogenesis and maintenance of the mitochondrial respiratory chain complexes. 2 Paraplegin deficiency in HSP does not result in the loss of m-AAA metalloprotease activity in brain mitochondria. The formation of m-AAA metaloproteases with altered substrate specificities probably leads to leads to axonal degeneration in HSP. 2 Pfefer G et al 4 showed SPG7 mutations caused increased mitochondrial biogenesis in muscle, with the clonal expansion of mitochondrial DNA mutations resulting in eye symptoms and myopathy. 9 There are only few studies to show whether clinical features mitochondrial dysfunction secondary to SPG 7 mutation becomes more prominent with growing age and if any phenotype genotype correlation exists or not. The complex phenotype of the SPG7 is associated with upper limb involvement, optic nerve involvement and cognitive deficit. 6 VanGassen Kl et al showed that a null mutation was associated with the co occurrence of cerebellar ataxia, a missense mutation of exon 10 resulted in predominant optic nerve atrophy. 10 However our cohort was too small to draw any such conclusion.
In conclusion, SPG 7 remains an important causes of undiagnosed ataxia.