Various types of mutations including aberrant splicing, gene deletion, frameshift, and nonsense mutations of
GRN have been reported. These mutations are known to cause familial FTLD via progranulin haploinsufficiency [
2,
3]. In the present case, our patient displayed PPA as a main symptom of progranulin haploinsufficiency due to a novel frameshift mutation of
GRN. PPA, progressive difficulties with word recall and usage, and language comprehension impairments were apparent, whereas behavioral disinhibition, executive function, and memory impairments were not impaired in the early stages of disease (within 1 year after diagnosis). Other diseases known to cause PPA include FTLD, Alzheimer’s disease (AD), CBS, and Creutzfeldt–Jakob disease (CJD) [
11]; however, a large number of studies reporting a link between
GRN mutations and PPA suggest that
GRN mutations should always be considered in the differential diagnosis of PPA. Similar symptoms, neuropsychological profile, and neuroimaging findings have been reported in a monozygotic twin pair with a
GRN mutation [
14]. In contrast, in our case, the patient’s brother presented distinct phenotypic characteristics (i.e., FTLD with PPA and CBS in the early stage). However, because the patient’s brother had already passed away, we could not obtain sufficient information to perform a genetic analysis. Table
1 provides a summary of known cases of
GRN mutations that have been associated with familial phenotypic heterogeneity. The presence of familial phenotypic heterogeneity with respect to symptoms such as cognitive dysfunction and motor impairment has been reported in 17 families with
GRN mutations [
4‐
10,
12‐
19]. These studies reported significant variations in age of onset and mutation site, and motor neuron diseases were relatively uncommon. Families have also been reported with differing symptom laterality and different regions of brain atrophy. In a genetic analysis of 48 Japanese families with FTLD, PSP, or CBS [
10], only one FTLD case with a
GRN mutation was identified. Therefore, familial FTLD associated with
GRN mutations is very rare. Furthermore, our report is the first to describe in detail distinct phenotypes within a family. Additional investigations of
GRN mutations mediating different clinical phenotypes of neurodegeneration within a family are necessary.
Table 1
Familial cases presenting with distinct clinical phenotypes
Rovelet-Lecrux et al., 2008 [ 15] | 67,77; 2 patients | Language dysfunction | PPA | left > right | French | g.95_4390del |
Resting tremor | PD |
| 45,73; 2 patients | Involuntary arm movement | CBS | right > left | N/A | g.26C >A |
Cognitive decline | AD |
| 54–67; 10 patients | Language dysfunction | PPA | left > right (n = 2) | United Kingdom | g.90_91insCTGC |
Limb apraxia | CBS | right > left (n = 1) |
Skoglund et al., 2009 [ 12] | 46–59; 10 patients | Language dysfunction | PPA | N/A | Swedish | g.102delC |
Limb apraxia | CBS |
Rademakers et al., 2007 [ 16] | 62,66; 2 patients | N/A | FTLD, CBS | N/A | American | g.3240C > T |
Masellis et al., 2006 [ 17] | 57,62; 2 patients | Behavioral changes | FTLD | right > left | Canadian family of Chinese origin | g.1637G > A |
Axial and extremity rigidity | CBS |
Leverenz et al., 2007 [ 18] | 35–69; 9 patients | Language dysfunction | FTLD | left > right (n = 3) right > left (n = 1) | American | g.1871A > G |
Anxiety, apathy | PPA |
Parkinsonism | PD |
López de Munain et al., 2008 [ 19] | 53,57; 2 patients | N/A | FTLD, CBS | N/A | Basque Country | g.1872G > A |
51,71; 2 patients | N/A | FTLD, CBS | N/A | Basque Country | g.1873G > A |
65; 2 patients | N/A | FTLD, CBS | N/A | Basque Country | g.1874G > A |
60; 2 patients | N/A | FTLD, CBS | N/A | Basque Country | g.1875G > A |
63–70; 4 patients | N/A | FTLD, CBS | N/A | Basque Country | g.1876G > A |
52; 2 patients | N/A | FTLD, ALS | N/A | Basque Country | g.1877G > A |
| 60–71; 5 patients | Language dysfunction | PPA | right > left | Italian | g.1977_1980delCACT |
Parkinsonism | CBS |
| N/A; 6 patients | N/A | FTLD, PD | symmetrical | American | g.2273_2274insTG |
N/A; 6 patients | N/A | FTLD, PD | right > left | American | g.2597delC |
Pietroboni et al., 2011 [ 7] | 47–79; 5 patients | Memory impairment, Acalculia | FTLD, AD | right > left (n = 1) symmetrical (n = 1) N/A (n = 3) | Italian | g.63_64insC |
Language impairment |
| 47–80; 6 patients | Behavioural abnormality | FTLD Dementia | Left > right | Italian | g.1761_1762delCA |
Language dysfunction |
Attention impairment |
The present case | 75,62; 2 patients | Language dysfunction | PPA | left > right | Japanese | g.1118_1119delCCinsG |
Limb apraxia | CBS |
As mentioned above, haploinsufficiency is thought to underlie the mechanism of
GRN mutation-associated FTLD. Haploinsufficiency is a cause of autosomal genetic conditions when the protein expressed by a single allele is not sufficient to maintain its normal function (loss of function) [
20]. On the other hand, in many autosomal dominant conditions, toxic gain of function or toxicity of excessive proteins are the cause of disease [
21,
22]. In fact, an approximate 50% decrease in mRNA and 33% decrease in progranulin protein was reported in one
GRN mutation carrier [
1,
2]. It has thus been suggested that an effective therapeutic strategy would be to increase progranulin levels in patients [
1]. The relationship between
GRN genetic variability and the risk of developing a neurodegenerative disease such as AD or MND has been reported [
1]. Yet, the exact functions of progranulin in the brain remain unclear, and its pathogenic involvement in neurodegenerative disorders is not known. Therefore, the accumulation of new cases of
GRN mutations that display distinct clinical phenotypes within a family may be helpful not only for the elucidation of progranulin function, but also for the development of replacement therapies in FTLD and other neurodegenerative diseases due to
GRN mutations.